CNV Pathogenicity Calculator

CNV Interpretation Scoring Rubric: Copy Number LOSS

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 loss content (For intragenic variants, use section 2E)	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/Predicted HI or Established Benign Genes/Genomic Regions (Skip to Section 3 if your copy number loss DOES NOT overlap these types of genes/regions)
Overlap with ESTABLISHED HI genes or genomic regions and consideration of reason for referral	2A. Complete overlap of an established HI gene/genomic region	1	1	Assigned points:
	2B. Partial overlap of an established HI genomic region The observed CNV does NOT contain the known causative gene or critical region for this established HI genomic region OR Unclear if known causative gene or critical region is affected OR No specific causative gene or critical region has been established for this HI genomic region (e.g. 1p36 deletion)	0	0
	2C. Partial overlap with the 5’ end of an established HI gene (3’ end of the gene not involved)...	See categories below
	2C-1. …and coding sequence is involved	0.90 (Range : 0.45 to 1.00)	1.00	Assigned points:
	2C-2. …and only the 5’ UTR is involved	0 (Range : 0 to 0.45)	0.45	Assigned points:
	2D. Partial overlap with the 3’ end of an established HI gene (5’ end of the gene not involved)…	See categories below
	2D-1. …and only the 3’ untranslated region is involved.	0 (Continue evaluation)	0
	2D-2. …and only the last exon is involved. Other established pathogenic variants have been reported in this exon.	0.90 (Range : 0.45 to 0.90)	0.90	Assigned points:
	2D-3. …and only the last exon is involved. No other established pathogenic variants have been reported in this exon.	0.30 (Range : 0 to 0.45)	0.45	Assigned points:
	2D-4. …and it includes other exons in addition to the last exon. Nonsense-mediated decay is expected to occur.	0.90 (Range : 0.45 to 1.00)	1.00	Assigned points:
	2E. Both breakpoints are within the same gene (gene-level sequence variant)	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) PVS1_Moderate or PM4 (in-frame indels) = 0.30 (Range: 0.15 to 0.45) PVS1_Supporting = 0.15 (Range: 0 to 0.30) N/A = No points, but continue evaluation	See categories at left	Assigned points:
Overlap with ESTABLISHED benign genes or genomic regions	2F. Completely contained within an established benign CNV region	-1	-1	Assigned points:
Overlap with ESTABLISHED benign genes or genomic regions	2G. Overlaps an established benign CNV, but includes additional genomic material	0 (Continue evaluation)	0
HI Predictors	2H. Multiple HI predictors suggest that AT LEAST ONE gene in the interval is haploinsufficient (HI)	0.15	0.15	Assigned points: 0
Section 3: Evaluation of Gene Number
Number of protein-coding RefSeq genes wholly or partially included in the copy number loss		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 (Skip to Section 5 if either your CNV overlapped with an established HI gene/region in Section 2, OR there have been no reports associating either the CNV or any genes within the CNV with human phenotypes caused by loss of function (LOF) or copy number loss)
Individual case evidence – de novo occurrences	Reported proband has either: A complete deletion of or a LOF variant within gene encompassed by the observed copy number loss OR an overlapping copy number loss similar in genomic content to the observed copy number loss 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 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)
	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)
Individual case evidence - inconsistent phenotype	4D.…the reported phenotype is NOT consistent with what is expected for 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 to 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 (without 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 (Range :0 to -1.00)	-1.00 (Total)	Assigned points:
Section 5: Evaluation of Inheritance Pattern/Family History for Patient Being Studied
Observed copy number loss 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 loss is INHERITED	5B. Patient with specific, well-defined phenotype and no family history. CNV 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. CNV is inherited from an apparently unaffected parent.	-0.15 (Range : 0 to -0.30)	-0.30 (total)	Assigned points:
	5D. CNV segregates with a consistent phenotype observed in the patient’s family.	Use segregation scoring categories from Section 4 (4F-4H) to determine score.	0.45	Assigned points:
Observed copy number loss – 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:
Other	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.	0.30 (Range : 0 to 0.30)	0.30	Assigned points:

Variant of Uncertain Significance
Total score: 0