Why use it

Helps clinicians quickly gauge the clinical relevance of a reported CNV when standard interpretive guidelines are needed at the point of care. This is a SCREENING/EDUCATIONAL tool; formal laboratory curation is always required.

About

Categorizes Copy Number Variants (Deletions or Duplications) identified on chromosomal microarray (CMA) into 5 standard tiers based on a simplified point-based scoring system inspired by ACMG/ClinGen technical standards (Riggs et al. 2020). Evaluates: CNV type, size, gene content, inheritance, overlap with known syndrome regions, and number of OMIM genes.

When to use

Reviewing microarray reports at the bedside.
Explaining CNV pathogenicity logic to patients and families.
Triaging CNVs for further workup in a clinical setting.
Teaching residents and fellows the principles of CNV classification.

Formula

Score = Gene Content Points + Size Points + Inheritance Points + Syndrome Region Points + Type Modifier Pathogenic ≥ 5 | Likely Pathogenic 3-4.9 | VUS 0-2.9 | Likely Benign -1 to -0.1 | Benign ≤ -1

Pearls & pitfalls

Deletions are generally less tolerated than duplications of the same region and size.
De novo status strongly increases pathogenicity, BUT confirm with maternity/paternity testing.
Inheritance from a HEALTHY parent pushes towards Benign but does not guarantee it (variable expressivity, incomplete penetrance).
Known syndrome region overlap (e.g., DiGeorge 22q11.2, Williams 7q11.23) is the strongest evidence for pathogenicity.
ClinGen curated haploinsufficiency (HI) and triplosensitivity (TS) scores should be checked for all OMIM genes in the interval.
Intragenic CNVs disrupting a single gene may be highly pathogenic even if small (<50kb).
CNVs in gene deserts or segmental duplications are more likely benign.
Compound heterozygosity: A deletion inherited from a healthy parent may unmask a recessive allele on the other chromosome.

Next steps

Pathogenic/Likely Pathogenic: Consider phenotype correlation and genetic counseling. VUS: May warrant parental studies, literature review, or ClinGen database check. Likely Benign/Benign: Generally reassuring but clinical correlation always required.

Evidence

Riggs ER et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the ACMG and ClinGen. Genet Med. 2020;22:245-257.

References

Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants. Genet Med. 2020;22:245-257.
Gardner RJM, Sutherland GR, Shaffer LG. Chromosome Abnormalities and Genetic Counseling. Chapter 17.

CNV Analytical Classification System

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