NM_004936.3:c.125G>A

CDKN2B · NP_004927.2:p.(Gly42Glu) · NM_004936.3

GRCh37: chr9:22008828 C>T · GRCh38: chr9:22008829 C>T

Gene: CDKN2B Transcript: NM_004936.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CDKN2B

Transcript

NM_004936.3

Protein

NP_004927.2:p.(Gly42Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The variant NM_004936.3:c.125G>A (p.Gly42Glu) in CDKN2B is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting strength.

Multiple in silico predictors consistently indicate a benign effect: REVEL 0.067, BayesDel -0.40492, and SpliceAI max delta 0.01, meeting BP4 at supporting benign strength.

The variant has not been reported in ClinVar, COSMIC, or the published literature. No functional data, segregation data, case-control data, or de novo observations are available.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is equivocal. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (c.125G>A, p.Gly42Glu) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant at the same amino acid position (Gly42) has been reported in ClinVar or the published literature, so PS1 cannot be applied.	clinvar
PS2	Not met	No parental or pedigree data are available to assess de novo occurrence of this variant.
PS3	Not met	No functional experimental data exist for this variant or for a systematically characterized range that includes residue Gly42. OncoKB reports Unknown Oncogenic Effect. No variant-specific functional studies were identified in the literature.	oncokb
PS4	Not met	No case-control or cohort data comparing the prevalence of this variant in affected individuals versus controls are available.
PS5	N/A	CDKN2B is associated with autosomal dominant cancer predisposition (renal cell carcinoma); it is not a recessive disorder gene. PS5 applies only to recessive disorders where the variant is found in trans with a pathogenic variant.
PM1	Not met	The variant is not located in a statistically significant mutational hotspot per cancerhotspots.org. No domain-level functional characterization data specific to the CDKN2B N-terminal region around residue Gly42 are available in the case evidence to support PM1 application.
PM2	Met	The variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting the PM2 threshold for a rare variant in a gene where the variant has not been observed in large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (Gly42) comparator variants with pathogenic classification were identified in ClinVar. PM5 candidate harvesting was not possible for this variant.	pm5_candidates
PM6	Not met	No de novo data are available for this variant; PM6 cannot be applied without a reported de novo observation.
PP1	Not met	No family segregation data are available to assess co-segregation of this variant with disease.
PP2	Not met	Insufficient data to apply PP2. Missense constraint metrics (z-score, HCI prior) are not available for CDKN2B; the HCI prior lookup returned 'gene_not_supported'. It cannot be determined whether this gene has a low rate of benign missense variation.
PP3	Not met	Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.067, BayesDel score -0.40492, and SpliceAI max delta 0.01. In silico evidence does not support a pathogenic role and instead supports benign through BP4.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical information is available to assess whether the individual's presentation is specific for a CDKN2B-associated disorder.
PP5	Not met	The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. The allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data on healthy adult carriers are available to assess whether this variant is observed in individuals without disease for a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrate that this variant has no damaging effect on protein function or splicing. In silico predictors alone are insufficient for BS3; they are captured under BP4.
BS4	Not met	No segregation data are available to assess lack of segregation with disease in affected family members.
BP1	Not met	CDKN2B germline missense variants are a recognized disease mechanism. PMID:25873077 identified germline missense mutations in CDKN2B predisposing to renal cell carcinoma. BP1 applies only when truncating variants are the sole known mechanism, which is not the case for CDKN2B.
BP2	Not met	No data are available on whether this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence consistently predict a benign effect: REVEL score 0.067 (benign range), BayesDel score -0.40492 (benign range), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico tools concordantly support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	The variant is absent from ClinVar; no reputable source has reported this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant (c.125G>A, p.Gly42Glu) is a missense substitution, not a synonymous variant.

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