ACMG CNV Classification wizard

Review and edit the ACMG Classification of a CNV

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

The ACMG CNV Classification wizard is located in the Evidence section of the Variant page. It is 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 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.

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

The ACMG SNV classification wizard features:

1. Automatically calculated ACMG class and score

1. 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

1. Reclassify button that enables Edit mode

1. 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

     
2. 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.

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:

   1. 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