NM_004936.3:c.338G>A (p.Gly113Asp) is a missense variant in exon 2 of CDKN2B, a tumor suppressor gene at 9p21.3 encoding the cyclin-dependent kinase inhibitor p15INK4b. This variant is extremely rare in large population databases: absent from gnomAD v2.1 and present at an allele frequency of 6.23×10⁻⁷ (1/1,606,290 alleles) in gnomAD v4.1, satisfying PM2 at moderate strength.1 Multiple lines of computational evidence suggest no significant impact on the gene product: BayesDel predicts a benign effect (−0.094), REVEL (0.484) falls below the commonly used pathogenic threshold of 0.5, and SpliceAI predicts no splicing alteration (max delta = 0.00), satisfying BP4 at supporting strength.2 This variant is absent from ClinVar with no submitter classifications, and has not been reported in the literature in association with disease.3 CDKN2B germline loss-of-function mutations have been associated with renal cell carcinoma (PMID:25873077), and 9p21.3 microdeletions encompassing CDKN2A/CDKN2B are associated with a cancer predisposition syndrome (PMID:35422439). However, the specific variant c.338G>A has not been reported in these or other published studies.4 No functional studies, case-control data, segregation data, or de novo reports are available for this variant. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), a single moderate pathogenic criterion (PM2) and a single supporting benign criterion (BP4) do not meet the threshold for Likely Pathogenic or Likely Benign; the variant is classified as a Variant of Uncertain Significance (VUS).5
CDKN2B
Final classification
VUS
CDKN2B c.338G>A · p.Gly113Asp
CDKN2B
NM_004936.3:c.338G>A (p.Gly113Asp) is a missense variant in exon 2 of CDKN2B, a tumor suppressor gene at 9p21.3 encoding the cyclin-dependent kinase inhibitor p15INK4b.
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDKN2B c.338G>A
PM2 + BP4
→
VUS
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
moderate
Pathogenic
This variant is extremely rare in large population databases: absent from gnomAD v2.1 (exomes) and present at an allele frequency of 6.23×10⁻⁷ (1/1,606,290 alleles, 0 homozygotes) in gnomAD v4.1, well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0.
gnomAD v2.1: absentgnomAD v4.1: 1/1606
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel (−0.094) predicts a benign effect. REVEL (0.484) falls below the commonly used pathogenic threshold of 0.5. SpliceAI (max delta = 0.00) predicts no splicing alteration.
BayesDel: −0.094 (benign)REVEL: 0.484 (below 0.5 pathogenic threshold)SpliceAI: max delta = 0.00 (no splicing impact)
Assessed · not applied
Pathogenic
PS1
No pathogenic variant at the same amino acid residue (Gly113) has been established to serve as a comparator for PS1.
PS2
No de novo occurrence of NM_004936.3:c.338G>A with confirmed parentage has been reported in a patient with a CDKN2B-associated phenotype.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect of NM_004936.3:c.338G>A (p.Gly113Asp) on CDKN2B protein function were identified.
PS4
No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals compared to controls were identified.
PM1
Residue Gly113 lies within the second ankyrin repeat domain (Ank 2, residues ~38-128) of CDKN2B, a region critical for CDK4/6 binding.
PM6
No de novo occurrence of NM_004936.3:c.338G>A (without confirmation of paternity) has been reported in a patient with a CDKN2B-associated phenotype.
PP1
No family studies demonstrating cosegregation of NM_004936.3:c.338G>A with a CDKN2B-associated phenotype across multiple affected relatives were identified.
PP2
Insufficient gene-level constraint data (e.g., gnomAD missense Z-score) are available to determine whether CDKN2B has a low rate of benign missense variation.
PP3
Computational evidence does not support a deleterious effect.
PP4
No patient phenotype or family history data are available for this assessment.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
BA1
The allele frequency in gnomAD v4.1 (6.23×10⁻⁷) is far below the 1% threshold for BA1.
BS1
The allele frequency in gnomAD v4.1 (6.23×10⁻⁷) is far below the 0.3% threshold for BS1.
BS2
No homozygous observations of this variant in gnomAD (0/1,606,290), and no observation of this variant in trans with a pathogenic CDKN2B variant.
BS3
No well-established functional studies demonstrating no damaging effect of NM_004936.3:c.338G>A (p.Gly113Asp) on CDKN2B protein function were identified.
BS4
No family segregation data are available to assess whether this variant fails to segregate with a CDKN2B-associated phenotype in affected family members.
BP1
Although CDKN2B is a tumor suppressor where loss-of-function is a known disease mechanism, pathogenic missense variants in the ankyrin repeat domains have been described that disrupt CDK4/6 binding.
BP2
No evidence of this variant observed in trans with a pathogenic CDKN2B variant for a fully penetrant dominant disorder was identified.
BP5
No evidence of this variant found in a case with an alternate molecular basis for disease was identified.
BP6
No reputable source has reported this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.22553e-07; MAF= 0.00006%, 1/1606290 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60328e-05; MAF= 0.00160%, 1/62372 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,606,290
0 hom
0 hom
Remaining individuals 1 / 62,372 |
0.0016% |
+ 9 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 = 0.00). REVEL score = 0.484. BayesDel score = -0.0936784.
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