3.11.7. Sample ACMG CNV Classifier

This algorithm computes classifications for each CNV based on the ACMG CNV guidelines published by ClinGen. These classifications are based on evidence such as population frequencies, conservation scores, and functional predictions. The 5 sections of criteria described by the ACMG CNV guidelines are used as the basis for classification and the recommended criteria for each CNV is presented alongside the classification.

Requirements

This algorithm requires that the VarSeq project contains at least one sample, and that CNVs have been called with the VarSeq CNV algorithm, or CNVs have been imported from an external caller.

Options

This algorithm allows the user to specify the following options:

  • Internal Database of Triplosensitive and Haploinsufficent Genes: Assessment catalog in which previous gene evaluations are stored. Genes with a Triplosensitive and/or Haploinsufficent will be used to determine if the region should be scored with section 2 criteria.

Output

  • Gene List: The list of the genes that the CNV overlaps.

  • Critical Gene List: The list of the genes with Triplosensitive and/or Haploinsufficent evidence that the CNV overlaps, these will be evaluated with the section 2 criteria.

  • Scored Gene: The gene from the Critical Gene List with the maximum score. This gene is selected as the most relevant.

  • Scored Gene Transcript: The transcript version used when evaluating the Scored Gene.

  • Scored Gene Impact Score: The score for the gene specific criteria that were applied to the CNV.

  • Additional Score: The score for criteria that were applied to the CNV as a whole, which are not specific to the Scored Gene.

  • Total Score: The sum of the Gene Score and the Additional Score.

  • Classification: The classification of the CNV based on the score.

    • Benign: a CNV with a score less than -1.

    • Likely Benign: a CNV with a score between -0.90 and -1.

    • VUS: (Variant of Unknown Significance) a CNV with a score between -0.90 and 0.90.

    • Likely Pathogenic: a CNV with a score between 0.90 and 1.

    • Pathogenic: a CNV with a score greater than 1.

  • Criteria: A list with the criteria applied followed by a brief explanation of why it was selected.

  • Potential Gene Impact Scores: The score for the gene, evaluated as if the gene has established evidence for HI/TS.

  • Potential Impact Criteria List: The criteria used to compute each of the gene impact scores, with a brief explanation.