ACMG CNV Classification wizard

Where can I review and edit the ACMG Classification of a CNV?

The ACMG CNV Classification wizard is located in the Evidence section of the Variant page. Itis available for tagged genomic variants.

The tool automatically scores sections 1, 2, 3, and partially scores sections 4 and 5 of the ACMG/Clingen guidelines, including the full PVS1 calculation required for intragenic variants. All the relevant data is summarized in an accessible table.

This tool is highly accurate and can save 75-90% of manual review time for CNVs (ASHG 2020 abstract).

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How do I review and edit the ACMG Classification of a CNV?

The ACMG CNV Classification wizard features:

1. Automatically calculated ACMG class | ACMG score

1. ACMG score sliderdepicting ranges of ACMG score values for each ACMG class and where the current classification falls: Benign: ≤-0.99; Likely Benign: -0.98...-0.90; VUS: -0.89...0.89; Likely Pathogenic: 0.90...0.98; Pathogenic: ≥0.99.

1. Reclassify button that enables Edit mode

1. Gene Number:

   • Number of protein-coding RefSeq genes overlapped by the CNV; of these:

     • Number of established ClinGen genes, i.e., genes with sufficient evidence of dosage sensitivity (defined by having ClinGen's Haploinsufficiency and/or Triplosensitivity scores of 3) or dosage insensitivity (scores of 40),
     • Number of predicted haploinsufficient genes (if applicable) - defined as genes with gnomAD probability of loss of function intolerance (pLI) score ≥0.9 and the DECIPHER HI index ≤10.00.
2. Genes affected by breakpoints - protein-coding RefSeq genes affected by CNV's breakpoints, and positions of breakpoints relative to the canonical transcript of each affected gene. Keep in mind that sometimes a breakpoint falls into more than one gene because genes may overlap.

1. 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.
2. Evidence sections. The wizard is designed to allow users to easily edit and rescore each section: a. In each section, the criterion selected is color-coded based on its score (hence, pathogenicity of the piece of evidence): * green indicates negative scores (benign evidence), * grey indicates zero (neutral evidence), and * red indicates positive scores (pathogenic evidence).

   b. Clicking on a section box reveals the active criterion, its score, and notes box. Here you can: i. add notes; ii. change the criterion's score where applicable*.

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c. With the _Edit tag_ option, users can modify a particular criterion: 1. select a different criterion within a section, 2. add notes, 3. change the criterion's score [where applicable\*](acmg_cnv_classification_wizard.md#h_6cd626ed23).

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d. You may choose to review and adjust 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.