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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.

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.

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].

#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

https://cirm.ucsc.edu/cgi-bin/hgTrackUi?db=hg19&g=iscaComposite

JSON Output

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.

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.

TSV Source files

Regions

Genes

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: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/help.shtml

Download URL

ftp://ftp.clinicalgenome.org/

JSON Output

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.

Here is a sample run:

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.

Here is a sample run:

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.

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

Source TSV

The source data comes in a CSV file that we convert to a TSV.

Download URL

https://search.clinicalgenome.org/kb/downloads#section_gene-disease-validity

Conflict Resolution

Multiple Classifications

Here is an example of multiple classifications.

In such cases, we select the more severe classification.

Multiple Dates

If the classifications are the same, we should select the latest classification date.

JSON Output

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.

Here is a sample run:

You can also use SAUtils command's subcommands AutoDownloadGenerate to generate ClinGen files. To use AutoDownloadGenerate, read more in SAUtils section.

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