Why use it

This is the standard laboratories are expected to apply and that reviewers, accreditors and ClinVar submissions are measured against. Making the arithmetic explicit also makes disagreement productive: two people who reach different classifications can see which section they scored differently, and by how much, instead of arguing about a gestalt impression.

About

The ACMG/ClinGen technical standard scores a constitutional copy-number LOSS across five evidence sections and sums the result into a single value that maps onto the five-tier classification. Section 1 asks whether the interval contains anything functionally important. Section 2 — usually decisive — scores overlap with genes and regions of established haploinsufficiency, and with established benign CNV regions. Section 3 weighs gene number. Section 4 accumulates case-level evidence from the literature, public databases and the laboratory's own records. Section 5 scores the inheritance of the variant in the patient being studied. Crucially, the point value of a criterion is not a constant: the standard publishes a suggested value and an allowed range, and the curator assigns a value within it. This calculator works the same way — every scored criterion accepts an assigned value, blank means the published suggestion, and section 4 enforces each criterion's ceiling so the total stays inside what the reference tool can produce.

When to use

Classifying a deletion reported on chromosomal microarray, exome or genome sequencing
Recording the evidence trail behind a CNV classification for a clinical report
Applying a laboratory judgement that deviates from a suggested point value, within the standard's allowed range
Re-evaluating a previously reported CNV after new case, segregation or population data
Laboratory variant review meetings, where the section-by-section score is the agenda

Formula

Total = Section 1 + Section 2 + Section 3 + Section 4 + Section 5 Every scored criterion contributes an ASSIGNED value inside its allowed range; blank uses the published suggestion. Section 4 criteria are individually capped. Pathogenic ≥ 0.99 Likely pathogenic 0.90 to 0.98 Uncertain significance −0.89 to 0.89 Likely benign −0.90 to −0.98 Benign ≤ −0.99

Pearls & pitfalls

Points are assigned, not fixed. Each criterion has a suggested value and a range; leaving the assignment blank here uses the suggestion, which is what reproduces the standard's worked examples.
Section 2 usually decides the outcome. A complete overlap of an established haploinsufficient gene or region (2A) suggests 1.00 on its own, which reaches Pathogenic without any other evidence.
Established haploinsufficiency means the ClinGen Dosage Sensitivity curation, not an impression from the literature. Check the gene and the region before applying 2A.
Section 4 criteria are CAPPED. Five reported probands under 4A do not score 2.25 — the criterion tops out at 0.90 however many observations support it. The cap is the point of the section: it stops a single well-published region from dominating the total.
Section 4 covers cases reported in the literature and databases; section 5 covers the patient in front of you. A de novo observation in a published proband (4A-4C) and a confirmed de novo in your own patient (5A) are different evidence and are scored separately — that is not double counting.
De novo is worth less when it is only assumed. Confirmed de novo with a highly specific phenotype suggests 0.45 per observation; the same observation with parentage unconfirmed suggests 0.30.
A deletion contained entirely within an established benign CNV region (2F) suggests −1.00 and reaches Benign on its own — the mirror image of 2A.
Section 3 counts genes, not size. A 5 Mb deletion in a gene desert scores nothing here; a gene-dense 2 Mb deletion can reach 0.90. The reference tool lets you assign anything from 0 to 0.90, with the gene-count tier as guidance.
Inheritance from an apparently unaffected parent (5B/5C) lowers the score but never settles the question: variable expressivity, incomplete penetrance and imprinting all produce exactly this pattern.
A statistically non-significant case–control study (4N, down to −0.90) is strong benign evidence and is easy to overlook, because negative results are the ones least likely to be sitting in the report in front of you.
The score is a summary of the evidence you entered, not a substitute for it. A confident total built on two poorly documented case reports is still a weak classification.

Next steps

Pathogenic / Likely pathogenic: report, correlate with phenotype, offer genetic counselling and parental testing where not already done. VUS: do not use for clinical decision-making; parental studies, literature review and periodic re-review are the routes out. Likely benign / Benign: generally not reported as causative. Record every criterion applied AND the value assigned to it — the score is only reproducible if both are written down.

Evidence

Riggs ER, Andersen EF, Cherry AM, et al. 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). Genet Med. 2020;22(2):245-257. Suggested values, allowed ranges and per-criterion caps follow the reference implementation at cnvcalc.clinicalgenome.org/cnvcalc/cnv-loss.

References

Riggs ER et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of ACMG and ClinGen. Genet Med. 2020;22(2):245-257. — link
Rehm HL et al. ClinGen — The Clinical Genome Resource. N Engl J Med. 2015;372(23):2235-2242. — link

ClinGen CNV Classification — Copy-Number LOSS

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