CNV Interpretation Scoring Rubric: Copy Number GAIN

Full descriptions of each evidence category, including caveats to consider while scoring and illustrative examples, are provided in Supplemental Material 1 [Word Document], published in the ACMG Technical Standards. Also visit the CNV Web Series page to access slides, webinars, examples, and FAQs.

Section 1: Initial Assessment of Genomic Content
Evidence Type Evidence Suggested points Max Score Points Given
Copy Number Gain Content (For intragenic variants, use section 2I) 1A. Contains protein-coding or other known functionally important elements 0 (Continue Evaluation) 0
1B. Does NOT contain protein-coding or any known functionally important elements -0.60 -0.60
Assigned points: 0
Section 2: Overlap with Established Triplosensitive (TS), Haploinsufficient (HI), or Benign Genes or Genomic Regions
Skip to Section 3 if the copy number gain does not overlap these types of genes/regions
Overlap with ESTABLISHED TS genes or genomic regions 2A. Complete overlap; the TS gene or minimal critical region is fully contained within the observed copy number gain 1 1
Assigned points:
2B. Partial overlap of an established TS region

  • The observed CNV does NOT contain the known causative gene or critical region for this established TS genomic region OR
  • Unclear if the known causative gene or critical region is affected OR
  • No specific causative gene or critical region has been established for this TS genomic region
 0 (Continue Evaluation) 0
Overlap with ESTABLISHED benign copy number gain genes or genomic regions 2C. Identical in gene content to the established benign copy number gain -1 -1
Assigned points:
2D. Smaller than established benign copy number gain, breakpoint(s) does not interrupt protein-coding genes -1 -1
Assigned points:
2E. Smaller than established benign copy number gain, breakpoint(s) potentially interrupts protein-coding gene 0 (Continue Evaluation) 0
2F. Larger than known benign copy number gain, does not include additional protein-coding genes -0.90 (Range: 0 to -1.00) -1
Assigned points:
2G. Overlaps a benign copy number gain but includes additional genomic material 0 (Continue Evaluation) 0
Overlap with ESTABLISHED HI gene(s)1 2H. HI gene fully contained within observed copy number gain 0 (Continue Evaluation) 0
Breakpoint(s) within ESTABLISHED HI genes 2I. Both breakpoints are within the same gene (gene-level sequence variant, possibly resulting in loss of function (LOF)) See ClinGen SVI working group PVS1 specifications
  • PVS1 = 0.90 (Range: 0.45 to 0.90)
  • PVS1_Strong = 0.45 (Range: 0.30 to 0.90)
  • N/A = 0 (Continue Evaluation)
    • Assigned points:
    2J. One breakpoint is within an established HI gene, patient’s phenotype is either inconsistent with what is expected for LOF of that gene OR unknown 0 (Continue evaluation) 0
    2K. One breakpoint is within an established HI gene, patient’s phenotype is highly specific and consistent with what is expected for LOF of that gene 0.45 0.45
    Assigned points:
    Breakpoints within other gene(s) 2L. One or both breakpoints are within gene(s) of no established clinical significance 0 (Continue evaluation) 0
    Section 3: Evaluation of Gene Number
    Number of protein-coding RefSeq genes wholly or partially included in the copy number gain Select number of genes from the pull-down menu Select number of genes from the pull-down menu
    Assigned points: 0
    Section 4: Detailed Evaluation of Genomic Content Using Published Literature, Public Databases, and/or Internal Lab Data
    Note: If there have been no reports associating either the copy number gain or any of the genes therein with human phenotypes caused by triplosensitivity, skip to Section 5.
    Individual case evidence – de novo occurrences Reported proband has either:
    • complete duplication of one or more genes within the observed copy number gain OR
    • an overlapping copy number gain similar in genomic content to the observed copy number gain AND…
    		See categories below
    4A. …the reported phenotype is highly specific and relatively unique to the gene or genomic region Confirmed de novo: 0.45 points each
    Assumed de novo: 0.30 points each (Range: 0.15 to 0.45)     		0.90 (Total)
    Assigned points:
    4B. …the reported phenotype is consistent with the gene/genomic region, is highly specific, but is not necessarily unique to the gene/genomic region Confirmed de novo: 0.30 points each
    Assumed de novo: 0.15 points each (Range: 0 to 0.45)     		0.90 (Total)
    Assigned points:
    4C. …the reported phenotype is consistent with the gene/genomic region, but not highly specific and/or with high genetic heterogeneity Confirmed de novo: 0.15 point each
    Assumed de novo: 0.10 points each (Range: 0 to 0.30)     		0.90 (Total)
    Assigned points:
    Individual case evidence - inconsistent phenotype 4D. …the reported phenotype is NOT consistent with the gene/genomic region or not consistent in general 0 points each (Range: 0 to -0.30) -0.30 (total)
    Assigned points:
    Individual case evidence – unknown inheritance 4E. Reported proband has a highly specific phenotype consistent with the gene/genomic region, but the inheritance of the variant is unknown. 0.10 points each (Range:0-0.15) 0.30 (total)
    Assigned points:
    Individual case evidence – segregation among similarly affected family members Select number of segregations from the pull-down menu Select number of segregations from the pull-down menu,
    Assigned points: 0
    Individual case evidence - Non-Segregations 4I. Variant is NOT found in another individual in the proband’s family AFFECTED with a consistent, specific, well-defined phenotype (no known phenocopies) -0.45 points per family
    (Range: 0 to -0.45)     		-0.90 (Total)
    Assigned points:
    4J. Variant IS found in another individual in the proband’s family UNAFFECTED with the specific, well-defined phenotype observed in the proband -0.30 points per family
    (Range: 0 to -0.30)     		-0.90 (Total)
    Assigned points:
    4K. Variant IS found in another individual in the proband’s family UNAFFECTED with the non-specific phenotype observed in the proband -0.15 points per family
    (Range: 0 to - 0.15)     		-0.30 (Total)
    Assigned points:
    Case-Control and Population Evidence 4L. Statistically significant increase amongst observations in cases (with a consistent, specific, well-defined phenotype) compared to controls 0.45 per study
    (Range: 0 to 0.45 per study)    		 0.45 (total)
    Assigned points:
    4M. Statistically significant increase amongst observations in cases (with a consistent, non-specific phenotype or unknown phenotype) compared to controls 0.30 per study
    (Range: 0 to 0.30 per study)    		 0.45 (total)
    Assigned points:
    4N. No statistically significant difference between observations in cases and controls -0.90 per study
    (Range: 0 to -0.90 per study)    		 -0.90 (total)
    Assigned points:
    4O. Overlap with common population variation -1.00 per study
    (Range: 0 to -1.00 per study)    		 -1.00 (total)
    Assigned points:
    Section 5: Evaluation of Inheritance Patterns/Family History for Patient Being Studied
    Observed copy number gain is DE NOVO 5A. Use appropriate category from de novo scoring section in Section 4. Use de novo scoring categories from Section 4 (4A-4D) to determine score. 0.45
    Assigned points:
    Observed copy number gain is INHERITED 5B. Patient with a specific, well-defined phenotype and no family history. Copy number gain is inherited from an apparently unaffected parent. -0.30 (Range: 0 to -0.45) -0.45
    Assigned points:
    5C. Patient with non-specific phenotype and no family history. Copy number gain is inherited from an apparently unaffected parent. -0.15 (Range: 0 to -0.30) -0.30
    Assigned points:
    5D. CNV segregates with consistent phenotype observed in the patient’s family Use segregation scoring categories from in Section 4 (4F-4H) to determine score. 0.45
    Assigned points:
    Observed copy number gain – Non-SEGREGATIONS 5E. Use appropriate category from non-segregation section in Section 4. Use non-segregation scoring categories from Section 4 (4I-4K) to determine score. -0.45
    Assigned points:
    5F. Inheritance information is unavailable or uninformative 0 0
    5G. Inheritance information is unavailable or uninformative. The patient phenotype is non-specific, but is consistent with what has been described in similar cases. 0.10 (Range: 0 to 0.15) 0.15
    Assigned points:
    5H. Inheritance information is unavailable or uninformative. The patient phenotype is highly specific and consistent with what has been described in similar cases. 0.15 (Range: 0 to 0.30) 0.30
    Assigned points:
    Variant of Uncertain Significance
    Total score: 0
    Variant of Uncertain Significance
    Total score: 0