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.1 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.2 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.3 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.4
CDKN2B
Final classification
VUS
CDKN2B c.125G>A · p.Gly42Glu
CDKN2B
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDKN2B c.125G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_004936.3 · variants mapped to exon structure
CDKN2B
NM_004936.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: absentgnomAD v4.1: absentgnomAD-Canada v1.0: absent (AC=0)
✓
BP4
supporting
Benign
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: 0.067 (benignthreshold >0.5 for pathogenic)BayesDel: -0.40492 (benign
Assessed · not applied
Pathogenic
PS1
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.
PS2
No parental or pedigree data are available to assess de novo occurrence of this variant.
PS3
No functional experimental data exist for this variant or for a systematically characterized range that includes residue Gly42.
PS4
No case-control or cohort data comparing the prevalence of this variant in affected individuals versus controls are available.
PM1
The variant is not located in a statistically significant mutational hotspot per cancerhotspots.org.
PM6
No de novo data are available for this variant; PM6 cannot be applied without a reported de novo observation.
PP1
No family segregation data are available to assess co-segregation of this variant with disease.
PP2
Insufficient data to apply PP2.
PP3
Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.067, BayesDel score -0.40492, and SpliceAI max delta 0.01.
PP4
No patient phenotype or clinical information is available to assess whether the individual's presentation is specific for a CDKN2B-associated disorder.
PP5
The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from all population databases.
BS2
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
No well-established functional studies demonstrate that this variant has no damaging effect on protein function or splicing.
BS4
No segregation data are available to assess lack of segregation with disease in affected family members.
BP1
CDKN2B germline missense variants are a recognized disease mechanism.
BP2
No data are available on whether this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6
The variant is absent from ClinVar; no reputable source has reported this variant as benign.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.067. BayesDel score = -0.40492.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDKN2B, a tumor suppressor and cell cycle regulator, is inactivated by mutation or deletion in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links