> For the complete documentation index, see [llms.txt](https://help.connected.illumina.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://help.connected.illumina.com/annotation/data-sources/clingen.md). # ClinGen ### Overview ClinGen is a National Institutes of Health (NIH)-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. {% hint style="info" %} **Publication** Heidi L. Rehm, Ph.D., Jonathan S. Berg, M.D., Ph.D., Lisa D. Brooks, Ph.D., Carlos D. Bustamante, Ph.D., James P. Evans, M.D., Ph.D., Melissa J. Landrum, Ph.D., David H. Ledbetter, Ph.D., Donna R. Maglott, Ph.D., Christa Lese Martin, Ph.D., Robert L. Nussbaum, M.D., Sharon E. Plon, M.D., Ph.D., Erin M. Ramos, Ph.D., Stephen T. Sherry, Ph.D., and Michael S. Watson, Ph.D., for ClinGen. **ClinGen The Clinical Genome Resource.** *N Engl J Med 2015; 372:2235-2242 June 4, 2015 DOI: 10.1056/NEJMsr1406261.* {% endhint %} ### ISCA Regions #### TSV Extraction ClinGen contains only copy number variation variants, since the coordinates in ClinGen original file follow the same rule as BED format, the coordinates had to be adjusted to \[BEGIN+1, END]. ```scss #bin chrom chromStart chromEnd name score strand thickStart thickEnd attrCount attrTags attrVals nsv530705 1 564405 8597804 0 1 copy_number_loss pathogenic False Developmental delay AND/OR other significant developmental or morphological phenotypes nsv530706 1 564424 3262790 0 1 copy_number_loss pathogenic False Abnormal facial shape,Abnormality of cardiac morphology,Global developmental delay,Muscular hypotonia HP:0001252,HP:0001263,HP:0001627,HP:0001999,MedGen:CN001147,MedGen:CN001157,MedGen:CN001482,MedGen:CN001810 nsv530707 1 564424 7068738 0 1 copy_number_loss pathogenic False Abnormality of cardiac morphology,Cleft upper lip,Failure to thrive,Global developmental delay,Intrauterine growth retardation,Microcephaly,Short stature HP:0000204,HP:0000252,HP:0001263,HP:0001508,HP:0001511,HP:0001627,HP:0004322,MedGen:C0349588,MedGen:C1845868,MedGen:C1853481,MedGen:C2364119,MedGen:CN000197,MedGen:CN001157,MedGen:CN001482 nsv533512 1 564435 649748 0 1 copy_number_loss benign False Developmental delay AND/OR other significant developmental or morphological phenotypes nsv931338 1 714078 4958499 0 1 copy_number_loss pathogenic False Developmental delay AND/OR other significant developmental or morphological phenotypes nsv530300 1 728138 5066371 1 0 copy_number_gain pathogenic False Abnormality of cardiac morphology,Cleft palate,Global developmental delay HP:0000175,HP:0001263,HP:0001627,MedGen:C2240378,MedGen:CN001157,MedGen:CN001482 ``` **Status levels** * benign * curated benign * curated pathogenic * likely benign * likely pathogenic * path gain * path loss * pathogenic * uncertain **Parsing** We parse the ClinGen tsv file and extract the following: * chrom * chromStart (note this a 0-based coordinate) * chromEnd * attrTags * attrVals `attrTags` and `attrVals` are comma separated lists. `attrTags` contains the field keys and `attrVals` contains the field values. We will parse the following keys from the two fields: * parent (this will be used as the ID in our JSON output) * clinical\_int * validated * phenotype (this should be a string array) * phenotype\_id (this should be a string array) Observed losses and observed gains will be calculated from entries that share a common parent ID. * variants with a common parent ID and same coordinates are grouped * calculated observed losses, observed gains for each group * Clinical significance and validation status are collapsed using the priority strategy described below * Variants with the same parent ID can have different coordinates (mapped to hg38) * nsv491508 : chr14:105583663-106881350 and chr14:105605043-106766076 (only one example) * we kept both variants ### Conflict Resolution #### Clinical significance priority When there are a mixture of variants belonging to the same parent ID, we will choose the most pathogenic clinical significance from the available values. i.e. if 3 samples were deemed pathogenic and 2 samples were likely pathogenic, we would list the variant as pathogenic. **Priority** (high to low) * Priority * Pathogenic * Likely pathogenic * Benign * Likely benign * Uncertain significance #### Validation Priority When there are a mixture of variants belonging to same parent ID, we will set the validation status to true if any of the variants were validated. #### Download URL #### JSON Output ```json "clingen":[ { "chromosome":"17", "begin":525, "end":14667519, "variantType":"copy_number_gain", "id":"nsv996083", "clinicalInterpretation":"pathogenic", "observedGains":1, "validated":true, "phenotypes":[ "Intrauterine growth retardation" ], "phenotypeIds":[ "HP:0001511", "MedGen:C1853481" ], "reciprocalOverlap":0.00131 }, { "chromosome":"17", "begin":45835, "end":7600330, "variantType":"copy_number_loss", "id":"nsv869419", "clinicalInterpretation":"pathogenic", "observedLosses":1, "validated":true, "phenotypes":[ "Developmental delay AND/OR other significant developmental or morphological phenotypes" ], "reciprocalOverlap":0.00254 } ] ``` | Field | Type | Notes | | ---------------------- | -------------- | -------------------------------------------------------------------------------------------------------------------------------- | | clingen | object array | | | chromosome | string | Ensembl-style chromosome names | | begin | integer | 1-based position | | end | integer | 1-based position | | variantType | string | Any of the sequence alterations defined here. | | id | string | Identifier from the data source. Alternatively a VID | | clinicalInterpretation | string | see possible values below | | observedGains | integer | Range: 0 - (231 - 1). Only used if copy\_number\_variation, copy\_number\_loss, or copy\_number\_gain. | | observedLosses | integer | Range: 0 - (231 - 1). Only used if copy\_number\_variation, copy\_number\_loss, or copy\_number\_gain. | | validated | boolean | | | phenotypes | string array | Description of the phenotype. | | phenotypeIds | string array | Description of the phenotype IDs. | | reciprocalOverlap | floating point | Range: 0 - 1. E.g. 0.57 would indicate a 57% reciprocal overlap. Specified up to 5 decimal places (Not reported for Insertions). | **clinicalInterpretation** * benign * curated benign * curated pathogenic * likely benign * likely pathogenic * path gain * path loss * pathogenic * uncertain ### Dosage Sensitivity Map The Clinical Genome Resource (ClinGen) consortium is curating genes and regions of the genome to assess whether there is evidence to support that these genes/regions are dosage sensitive and should be targeted on a cytogenomic array. Illumina Connected Annotations reports these annotations for overlapping SVs. {% hint style="info" %} **Publication** Riggs ER, Nelson T, Merz A, Ackley T, Bunke B, Collins CD, Collinson MN, Fan YS, Goodenberger ML, Golden DM, Haglund-Hazy L, Krgovic D, Lamb AN, Lewis Z, Li G, Liu Y, Meck J, Neufeld-Kaiser W, Runke CK, Sanmann JN, Stavropoulos DJ, Strong E, Su M, Tayeh MK, Kokalj Vokac N, Thorland EC, Andersen E, Martin CL. **Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar.** *Hum Mutat. 2018 Nov;39(11):1650-1659. doi: 10.1002/humu.23610. PMID: 30095202; PMCID: PMC7374944.* {% endhint %} #### TSV Source files **Regions** ```scss #ClinGen Region Curation Results #07 May,2019 #Genomic Locations are reported on GRCh38 (hg38): GCF_000001405.36 #https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen #to create link: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/clingen_region.cgi?id=key #ISCA ID ISCA Region Name cytoBand Genomic Location Haploinsufficiency Score Haploinsufficiency Description Haploinsufficiency PMID1 Haploinsufficiency PMID2 Haploinsufficiency PMID3 Triplosensitivity Score Triplosensitivity Description Triplosensitivity PMID1 Triplosensitivity PMID2 Triplosensitivity PMID3 Date Last Evaluated Loss phenotype OMIM ID Triplosensitive phenotype OMIM ID ISCA-46299 Xp11.22 region (includes HUWE1) Xp11.22 tbd 0 No evidence available 3 Sufficient evidence for dosage pathogenicity 22840365 20655035 26692240 2018-11-19 ISCA-46295 15q13.3 recurrent region (D-CHRNA7 to BP5) (includes CHRNA7 and OTUD7A) 15q13.3 chr15:31727418-32153204 3 Sufficient evidence for dosage pathogenicity 19898479 20236110 22775350 40 Dosage sensitivity unlikely 26968334 22420048 2018-05-10 ISCA-46291 7q11.23 recurrent distal region (includes HIP1, YWHAG) 7q11.23 chr7:75528718-76433859 2 Some evidence for dosage pathogenicity 21109226 16971481 1 Little evidence for dosage pathogenicity 21109226 27867344 2018-12-31 ISCA-46290 Xp11.22p11.23 recurrent region (includes SHROOM4) Xp11.22-p11.23 chrX: 48447780-52444264 0 No evidence available 3 Sufficient evidence for dosage pathogenicity 19716111 21418194 25425167 2017-12-14 300801 ``` **Genes** ```scss #ClinGen Gene Curation Results #24 May,2019 #Genomic Locations are reported on GRCh37 (hg19): GCF_000001405.13 #https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen #to create link: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/clingen_gene.cgi?sym=Gene Symbol #Gene Symbol Gene ID cytoBand Genomic Location Haploinsufficiency Score Haploinsufficiency Description Haploinsufficiency PMID1 Haploinsufficiency PMID2 Haploinsufficiency PMID3 Triplosensitivity Score Triplosensitivity Description Triplosensitivity PMID1 Triplosensitivity PMID2 Triplosensitivity PMID3 Date Last Evaluated Loss phenotype OMIM ID Triplosensitive phenotype OMIM ID A4GALT 53947 22q13.2 chr22:43088121-43117307 30 Gene associated with autosomal recessive phenotype 0 No evidence available 2014-12-11 111400 AAGAB 79719 15q23 chr15:67493013-67547536 3 Sufficient evidence for dosage pathogenicity 23064416 23000146 0 No evidence available 2013-02-28 148600 ``` #### Dosage Rating System | Rating | Possible Clinical Interpretation | | ------ | --------------------------------------------------------------------------------------- | | 0 | No evidence to suggest that dosage sensitivity is associated with clinical phenotype | | 1 | Little evidence suggesting dosage sensitivity is associated with clinical phenotype | | 2 | Emerging evidence suggesting dosage sensitivity is associated with clinical phenotype | | 3 | Sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype | | 30 | Gene associated with autosomal recessive phenotype | | 40 | Dosage sensitivity unlikely | Reference: #### Download URL #### JSON Output ```json "clingenDosageSensitivityMap": [{ "chromosome": "15", "begin": 30900686, "end": 32153204, "haploinsufficiency": "sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype", "triplosensitivity": "little evidence suggesting dosage sensitivity is associated with clinical phenotype", "reciprocalOverlap": 0.00147, "annotationOverlap": 0.33994 }, { "chromosome": "15", "begin": 31727418, "end": 32153204, "haploinsufficiency": "sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype", "triplosensitivity": "dosage sensitivity unlikely", "reciprocalOverlap": 0.00147, "annotationOverlap": 1 }] ``` | Field | Type | Notes | | --------------------------- | -------------- | -------------------------------------------------------------------------------------------------------------------------------- | | clingenDosageSensitivityMap | object array | | | chromosome | string | Ensembl-style chromosome names | | begin | integer | 1-based position | | end | integer | 1-based position | | haploinsufficiency | string | see possible values below | | triplosensitivity | string | (same as haploinsufficiency) | | reciprocalOverlap | floating point | Range: 0 - 1. E.g. 0.57 would indicate a 57% reciprocal overlap. Specified up to 5 decimal places (Not reported for Insertions). | | annotationOverlap | floating point | Range: 0 - 1. E.g. 0.57 would indicate a 57% reciprocal overlap. Specified up to 5 decimal places (Not reported for Insertions). | **haploinsufficiency and triplosensitivity** * no evidence to suggest that dosage sensitivity is associated with clinical phenotype * little evidence suggesting dosage sensitivity is associated with clinical phenotype * emerging evidence suggesting dosage sensitivity is associated with clinical phenotype * sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype * gene associated with autosomal recessive phenotype * dosage sensitivity unlikely #### Building the supplementary files The gene dosage sensitivity `.nga` for Illumina Connected Annotations can be built using the `SAUtils` command's `DosageSensitivity` subcommand. The required data file is `ClinGen_gene_curation_list_{ASSEMBLY}.tsv` (url provided above) and its associated `.version` file. ```scss NAME=ClinGen Dosage Sensitivity Map VERSION=20211201 DATE=2021-12-01 DESCRIPTION=Dosage sensitivity map from ClinGen (dbVar) ``` Here is a sample run: ```scss dotnet SAUtils.dll DosageSensitivity --------------------------------------------------------------------------- SAUtils (c) 2023 Illumina, Inc. Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al 3.21.0-0-gd2a0e953 --------------------------------------------------------------------------- USAGE: dotnet SAUtils.dll dosagesensitivity [options] Creates a gene annotation database from dbVar data OPTIONS: --tsv, -t input tsv file --out, -o output directory --help, -h displays the help menu --version, -v displays the version dotnet SAUtils.dll DosageSensitivity --out SupplementaryDatabase/64/GRCh37 --tsv ClinGen_gene_curation_list_GRCh37.tsv --------------------------------------------------------------------------- SAUtils (c) 2023 Illumina, Inc. Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al 3.21.0-0-gd2a0e953 --------------------------------------------------------------------------- Time: 00:00:00.1 ``` For building the `.nsi` files, we use the `SAUtils` command's `DosageMapRegions` subcommand. The required data file is `ClinGen_region_curation_list_{ASSEMBLY}.tsv` (url provided above) and its associated `.version` file. ```scss NAME=ClinGen Dosage Sensitivity Map VERSION=20211201 DATE=2021-12-01 DESCRIPTION=Dosage sensitivity map from ClinGen (dbVar) ``` Here is a sample run: ```scss dotnet SAUtils.dll DosageMapRegions --------------------------------------------------------------------------- SAUtils (c) 2023 Illumina, Inc. Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al 3.21.0-0-gd2a0e953 --------------------------------------------------------------------------- USAGE: dotnet SAUtils.dll dosagemapregions [options] Creates an interval annotation database from dbVar data OPTIONS: --tsv, -t input tsv file --ref, -r input reference filename --out, -o output directory --help, -h displays the help menu --version, -v displays the version dotnet SAUtils.dll DosageMapRegions --out SupplementaryDatabase/64/GRCh37 --ref References/7/Homo_sapiens.GRCh37.Nirvana.dat --tsv ClinGen_region_curation_list_GRCh37.tsv --------------------------------------------------------------------------- SAUtils (c) 2023 Illumina, Inc. Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al 3.21.0-0-gd2a0e953 --------------------------------------------------------------------------- Writing 505 intervals to database... Time: 00:00:00.1 ``` You can also use `SAUtils` command's subcommands `AutoDownloadGenerate` to generate ClinGen files. To use `AutoDownloadGenerate`, read more in `SAUtils` section. ### Gene-Disease Validity The ClinGen Gene-Disease Clinical Validity curation process involves evaluating the strength of evidence supporting or refuting a claim that variation in a particular gene causes a particular disease. Illumina Connected Annotations reports these annotations for genes in the genes section of the JSON. {% hint style="info" %} **Publication** Strande NT, Riggs ER, Buchanan AH, et al. **Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.** *Am J Hum Genet. 2017;100(6):895-906. doi:10.1016/j.ajhg.2017.04.015* {% endhint %} #### Source TSV The source data comes in a CSV file that we convert to a TSV. ```scss CLINGEN GENE VALIDITY CURATIONS FILE CREATED: 2019-05-28 WEBPAGE: https://search.clinicalgenome.org/kb/gene-validity +++++++++++,++++++++++++++,+++++++++++++,++++++++++++++++++,+++++++++,++++++++++++++,+++++++++++++,+++++++++++++++++++ GENE SYMBOL,GENE ID (HGNC),DISEASE LABEL,DISEASE ID (MONDO),SOP,CLASSIFICATION,ONLINE REPORT,CLASSIFICATION DATE +++++++++++,++++++++++++++,+++++++++++++,++++++++++++++++++,+++++++++,++++++++++++++,+++++++++++++,+++++++++++++++++++ A2ML1,HGNC:23336,Noonan syndrome with multiple lentigines,MONDO_0007893,SOP5,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/59b87033-dd91-4f1e-aec1-c9b1f5124b16--2018-06-07T14:37:47,2018-06-07T14:37:47.175Z A2ML1,HGNC:23336,cardiofaciocutaneous syndrome,MONDO_0015280,SOP5,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/fc3c41d8-8497-489b-a350-c9e30016bc6a--2018-06-07T14:31:03,2018-06-07T14:31:03.696Z A2ML1,HGNC:23336,Costello syndrome,MONDO_0009026,SOP5,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/ea72ba8d-cf62-44bc-86be-da64e3848eba--2018-06-07T14:34:05,2018-06-07T14:34:05.324Z ``` #### Download URL #### Conflict Resolution **Multiple Classifications** Here is an example of multiple classifications. ```scss $ grep MONDO_0010192 ClinGen-Gene-Disease-Summary-2019-12-02.csv | grep EDNRB EDNRB,HGNC:3180,Waardenburg syndrome type 4A,MONDO_0010192,SOP6,Moderate,https://search.clinicalgenome.org/kb/gene-validity/d7abbd45-7915-437b-849b-dea876bfc2f5--2018-05-08T04:00:00,2018-05-08T04:00:00.000Z EDNRB,HGNC:3180,Waardenburg syndrome type 4A,MONDO_0010192,SOP6,Limited,https://search.clinicalgenome.org/kb/gene-validity/73ee9727-60c1-40fd-830f-08c2b513d2ee--2018-05-08T04:00:00,2018-05-08T04:00:00.000Z ``` In such cases, we select the more severe classification. **Multiple Dates** ```scss $ grep MONDO_0016419 ClinGen-Gene-Disease-Summary-2019-12-02.csv | grep MUTYH MUTYH,HGNC:7527,hereditary breast carcinoma,MONDO_0016419,SOP4,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/9904,2017-05-24T00:00:00 MUTYH,HGNC:7527,hereditary breast carcinoma,MONDO_0016419,SOP4,No Reported Evidence,https://search.clinicalgenome.org/kb/gene-validity/9902,2017-05-25T00:00:00 ``` If the classifications are the same, we should select the latest classification date. #### JSON Output ```json "clingenGeneValidity":[ { "diseaseId":"MONDO_0007893", "disease":"Noonan syndrome with multiple lentigines", "classification":"no reported evidence", "classificationDate":"2018-06-07" }, { "diseaseId":"MONDO_0015280", "disease":"cardiofaciocutaneous syndrome", "classification":"no reported evidence", "classificationDate":"2018-06-07" } ] ``` | Field | Type | Notes | | ------------------- | ------ | ----------------------------------- | | clingenGeneValidity | object | | | diseaseId | string | Monarch Disease Ontology ID (MONDO) | | disease | string | disease label | | classification | string | see below for possible values | | classificationDate | string | yyyy-MM-dd | **classification** * no reported evidence * disputed * limited * moderate * definitive * strong * refuted * no known disease relationship #### Building the supplementary files The gene disease validity `.nga` for Illumina Connected Annotations can be built using the `SAUtils` command's `DiseaseValidity` subcommand. The only required data file is `Clingen-Gene-Disease-Summary-2021-12-01.tsv` (url provided above) and its associated `.version` file. ```scss NAME=ClinGen disease validity curations VERSION=20211201 DATE=2021-12-01 DESCRIPTION=Disease validity curations from ClinGen (dbVar) ``` Here is a sample run: ```scss dotnet SAUtils.dll DiseaseValidity --------------------------------------------------------------------------- SAUtils (c) 2023 Illumina, Inc. Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al 3.21.0-0-gd2a0e953 --------------------------------------------------------------------------- USAGE: dotnet SAUtils.dll diseasevalidity [options] Creates a gene annotation database from ClinGen gene validity data OPTIONS: --csv, -i ClinGen gene validity file path --cache, -c input cache directory --ref, -r input reference filename --out, -o output directory --help, -h displays the help menu --version, -v displays the version dotnet SAUtils.dll DiseaseValidity --tsv Clingen-Gene-Disease-Summary-2021-12-01.tsv \\ --uga Cache --out SupplementaryDatabase --------------------------------------------------------------------------- SAUtils (c) 2023 Illumina, Inc. Stromberg, Roy, Platzer, Siddiqui, Ouyang, et al 3.21.0-0-gd2a0e953 --------------------------------------------------------------------------- Number of geneIds missing from the cache:0 (0%) Time: 00:00:00.2 ``` You can also use `SAUtils` command's subcommands `AutoDownloadGenerate` to generate ClinGen files. To use `AutoDownloadGenerate`, read more in `SAUtils` section. --- # Agent Instructions This documentation is published with GitBook. GitBook is the documentation platform designed so that both humans and AI agents can read, navigate, and reason over technical content effectively. Learn more at gitbook.com. ## Querying This Documentation If you need additional information that is not directly available in this page, you can query the documentation dynamically by asking a question. Perform an HTTP GET request on the current page URL with the `ask` query parameter, and the optional `goal` query parameter: ``` GET https://help.connected.illumina.com/annotation/data-sources/clingen.md?ask=&goal= ``` `ask` is the immediate question: it should be specific, self-contained, and written in natural language. `goal` is optional and describes the broader end goal you are ultimately trying to accomplish on behalf of the user. GitBook uses it to tailor the answer towards what is most useful for that goal. The response will contain a direct answer to the question and relevant excerpts and sources from the documentation. Use this mechanism when the answer is not explicitly present in the current page, you need clarification or additional context, or you want to retrieve related documentation sections.