ACMG CNV Classification wizard
The ACMG CNV Classification wizard is located in the Evidence tab of the Variant page. It is available for tagged genomic variants.
The tool automatically scores sections 1, 2, and 3, and partially scores sections 4 and 5 of the ACMG/ClinGen guidelines, including the full PVS1 calculation required for intragenic variants. All relevant data is summarized in an accessible table.
CNV classification follows the ACMG/ClinGen technical standards described in Riggs et al., 2020 (PMID: 31690835).
This tool is designed to save significant review time, reducing manual effort by up to 75–90% (ASHG 2020 abstract).
Factors considered in CNV scoring
When determining the automated classification, the system considers:
Inheritance patterns – whether the CNV is de novo or segregates in a family
Gene content – the number and type of genes affected, including ClinGen dosage sensitivity and predicted haploinsufficient genes
Overlap with known pathogenic regions – alignment with established genomic regions linked to disease
By combining these elements, the scoring logic provides a clearer and more consistent starting point for CNV interpretation.
Tip: Automated scoring provides a strong baseline, but it may not capture every detail of a case. Consider adjusting the classification manually if:
Family inheritance information is incomplete or uncertain
Breakpoint overlaps are ambiguous or affect multiple overlapping genes
New literature or curated evidence suggests a different pathogenicity than what is auto-assigned
Manual review ensures that edge cases are interpreted accurately and remain clinically relevant.
Warning: Automated CNV scoring relies heavily on reference databases such as ClinGen, DECIPHER, and gnomAD. If a gene or region is not yet well-curated in these databases, the classification may be incomplete or misleading. Always confirm key findings with manual review and supporting evidence before final reporting.
How to review and edit the ACMG Classification of a CNV
The ACMG CNV classification wizard includes:
Automatically calculated ACMG class and score
ACMG score slider that shows the ranges of ACMG values for each classification and highlights where the current CNV falls:
Benign: ≤ –0.99
Likely Benign: –0.98…–0.90
VUS: –0.89…0.89
Likely Pathogenic: 0.90…0.98
Pathogenic: ≥ 0.99
Reclassify button that enables Edit mode
Gene Number:
Gene Number shows the total protein-coding RefSeq genes overlapped by the CNV. Of these:
Established ClinGen genes (dosage sensitivity or insensitivity defined by ClinGen scores)
Predicted haploinsufficient genes, based on gnomAD pLI ≥ 0.9 and DECIPHER HI index ≤ 10
Genes affected by breakpoints
This lists the protein-coding RefSeq genes that are directly impacted at the CNV breakpoints. For each gene, the wizard shows where the breakpoint occurs in relation to the gene’s canonical transcript. Note that in some cases a breakpoint may fall within more than one gene, since genes can overlap in the genome.
Gene table that provides a summary of the affected protein-coding genes:
Gene description:
Name - HGNC gene symbol,
Strand orientation;
Overlap info:
Gene - percentage of a gene involved in a CNV,
CNV - percentage of a CNV that overlaps with a gene;
ClinGen dosage sensitivity scores:
TS - ClinGen triplosensitivity score,
HI - ClinGen haploinsufficiency score;
HI predictors:
gnomAD pLI score (colored in red if pLI > 0.9),
DECIPHER HI index (colored in red if HI < 10);
Canonical transcript:
RefSeq ID,
5’ UTR - affected or not,
CDS:
exons involved out of total,
NMD flag if the CNV is predicted to undergo nonsense mediated decay.
ClinVar flag if there are Clinvar Path SNV in the last exon
3’ UTR - affected or not.
Evidence sections:
Color - coded criteria
Green = benign evidence
Grey = neutral evidence
Red = pathogenic evidence
b. Clicking on a section box reveals the active criterion, its score, and notes box. Here you can:
Add notes
Change the criterion's score where applicable*
Select a different criterion with the 'Edit tag' option
You may also reclassify the CNV by adjusting evidence section-by-section using the Reclassify option
*Criteria with variable score:
2F, 2I
4A, 4B, 4C, 4D, 4E, 4I, 4J, 4K, 4L, 4M, 4N, 4O
5A, 5B, 5C, 5E, 5G, 5H
Learn more
ACMG SNV Classification wizard
Compare the SNV ACMG workflow for reviewing tags, strengths, and final classification.
Logic behind ACMG classification of SNVs
Review the SNV score thresholds, combination rules, and classification logic.
Individual ACMG criteria evaluation
Explore detailed explanations for individual ACMG criteria used in SNV interpretation.
Evidence tab
Return to the Evidence tab overview for related interpretation workflows and tools.
Disease source used in ACMG evaluation
When a gene–disease association is available from multiple databases (for example: OMIM, CGD, Orphanet etc.), the Gene-related diseases card in the Variant Page display all available disease sources. Although multiple disease entries may appear, ACMG inheritance-based logic relies exclusively on the OMIM disease entry to determine the mode of inheritance.
ACMG rule evaluation uses only the OMIM source when assessing inheritance-dependent evidence.
If OMIM does not contain a pre-populated inheritance mode, ACMG rules that depend on inheritance will not be triggered, even if inheritance information exists in another disease source.
Impact on ACMG evaluation - CNVs
For copy number variants (CNVs), inheritance information plays a central role in the ACMG/ClinGen CNV scoring framework. Unlike SNVs, CNV interpretation incorporates inheritance as explicit scoring evidence that can increase or decrease support for pathogenicity.
Inheritance information derived from OMIM influences the following CNV evidence categories:
De novo CNVs (5A) CNVs identified as de novo provide positive evidence toward pathogenicity. Accurate inheritance determination is required to apply this evidence.
Inherited CNVs from an unaffected parent (5B-5C) CNVs inherited from an apparently unaffected parent contribute negative evidence, reducing support for pathogenicity in many disease contexts.
Segregation with phenotype (5D) CNVs that segregate with disease within a family add supportive evidence toward pathogenic classification.
Lack of segregation (5E) CNVs that do not segregate with affected family members weaken pathogenicity evidence.
Uninformative or phenotype-based inheritance (5F-5H) When inheritance data is missing or unclear, inheritance-based evidence may not be applied, and classification relies more heavily on genomic content and phenotype consistency.
Warning: If OMIM does not define an inheritance mode for the associated disease, inheritance-based CNV scoring components may not be applied, even if inheritance information is available from other disease sources.
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