Table 2:

CNV Interpretation Scoring Metric- Copy Number GAIN

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
Section 1: Initial Assessment of Genomic Content
Evidence Type	Evidence	Suggested Points/Case	Max Score
Copy Number Gain Content	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
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
	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
	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 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)
	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
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	3A. 0-34 genes	0	0
	3B. 35-49 genes	0.45	0.45
	3C. 50 or more genes	0.90	0.90
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 occurrences	Reported 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 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)
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 to 0.15)	0.30 (total)
Individual case evidence – segregation among similarly affected family members	4F. 3-4 observed segregations	0.15	0.45
	4G. 5-6 observed segregations	0.30
	4H. 7 or more observed segregations	0.45
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)
	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 non-specific phenotype observed in the proband	−0.15 points per family (Range: 0 to −0.15)	−0.30 (total)
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)
	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)
	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 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
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
	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
	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
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
	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
	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

Note: Only those CNVs otherwise meeting the reporting thresholds determined by your laboratory should be evaluated using this metric.

See Supplemental Material 1 for full description of each evidence category.