Table 2 CNV interpretation scoring metric: copy-number gain

From: Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)

Section 1: Initial assessment of genomic content
Evidence typeEvidenceSuggested points/caseMax score
Copy-number gain content1A. 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
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 regions2A. Complete overlap; the TS gene or minimal critical region is fully contained within the observed copy-number gain.11
 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 regions2C. Identical in gene content to the established benign copy-number gain.−1−1
 2D. Smaller than established benign copy-number gain, breakpoint(s) does not interrupt protein-coding genes.−1−1
 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.−1 (range: 0 to −1.00)−1
 2G. Overlaps a benign copy-number gain but includes additional genomic material.0 (Continue evaluation)0
Overlap with ESTABLISHED HI gene(s)2H. HI gene fully contained within observed copy-number gain.0 (Continue evaluation)0
Breakpoint(s) within ESTABLISHED HI genes2I. 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)
 
 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.0.450.45
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 gain3A. 0–34 genes00
 3B. 35–49 genes0.450.45
 3C. 50 or more genes0.900.90
Section 4: Detailed evaluation of genomic content using cases from 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 occurrencesReported proband (from literature, public databases, or internal lab data) 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)
 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 point each (range: 0 to 0.45)
 
 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 point each (range: 0 to 0.30)
 
Individual case evidence—inconsistent phenotype4D. …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)
Individual case evidence—unknown inheritance4E. 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 to 0.15)0.30 (total)
Individual case evidence—segregation among similarly affected family members4F. 3–4 observed segregations0.150.45
 4G. 5–6 observed segregations0.30 
 4H. 7 or more observed segregations0.45 
Individual case evidence—nonsegregations4I. 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)
 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)
 4K. Variant IS found in another individual in the proband’s family UNAFFECTED with the nonspecific phenotype observed in the proband.−0.15 points per family (range: 0 to −0.15)−0.30 (total)
Case–control and population evidence4L. Statistically significant increase among observations in cases (with a consistent, specific, well-defined phenotype) compared with controls.0.45 per study (range: 0 to 0.45 per study)0.45 (total)
 4M. Statistically significant increase among observations in cases (with a consistent, nonspecific phenotype or unknown phenotype) compared with controls.0.30 per study (range: 0 to 0.30 per study)0.45 (total)
 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)
 4O. Overlap with common population variation.−1 (range: 0 to −1)−1
Section 5: Evaluation of inheritance patterns/family history for patient being studied
Observed copy-number gain is de novo5A. Use appropriate category from de novo scoring section in section 4.Use de novo scoring categories from section 4 (4A–4D) to determine score0.45
Observed copy-number gain is inherited5B. 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
 5C. Patient with nonspecific phenotype and no family history. Copy-number gain is inherited from an apparently unaffected parent.−0.15 (range: 0 to −0.30)−0.30
 5D. CNV segregates with consistent phenotype observed in the patient’s family.Use segregation scoring categories from in section 4 (4F–4H) to determine score0.45
Observed copy-number gain—nonsegregations5E. Use appropriate category from nonsegregation section in section 4.Use nonsegregation scoring categories from section 4 (4I–4K) to determine score−0.45
 5F. Inheritance information is unavailable or uninformative.00
 5G. Inheritance information is unavailable or uninformative. The patient phenotype is nonspecific, but is consistent with what has been described in similar cases.0.10 (range: 0 to 0.15)0.15
 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
  1. Only those CNVs otherwise meeting the reporting thresholds determined by your laboratory should be evaluated using this metric. See Supplemental Material 1for full description of each evidence category. Scoring: pathogenic 0.99 or more points, likely pathogenic 0.90 to 0.98 points,variant of uncertain significance 0.89 to −0.89 points, likely benign −0.90 to −0.98 points,benign −0.99 or fewer points.
  2. CNV copy-number variant,SVI sequence variant interpretation.