NM_004936.3:c.338G>A

CDKN2B · NP_004927.2:p.(Gly113Asp) · NM_004936.3

GRCh37: chr9:22006065 C>T · GRCh38: chr9:22006066 C>T

Gene: CDKN2B Transcript: NM_004936.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

CDKN2B

Transcript

NM_004936.3

Protein

NP_004927.2:p.(Gly113Asp)

gnomAD AF

6.225525901300513e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

This variant is absent from ClinVar with no submitter classifications, and has not been reported in the literature in association with disease.

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.

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).

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	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). NM_004936.3:c.338G>A is a missense variant (p.Gly113Asp) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No pathogenic variant at the same amino acid residue (Gly113) has been established to serve as a comparator for PS1. ClinVar contains no entries for CDKN2B at this residue, and no literature reports a pathogenic variant at Gly113.	clinvar
PS2	Not assessed	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	Not assessed	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	Not met	No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals compared to controls were identified. The variant is absent from ClinVar with no submitter-reported case counts.	clinvar
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no diagnostic laboratory has submitted a pathogenic interpretation.	clinvar
PM1	Not assessed	Residue Gly113 lies within the second ankyrin repeat domain (Ank 2, residues ~38-128) of CDKN2B, a region critical for CDK4/6 binding. However, no evidence of a well-established mutational hotspot with multiple pathogenic missense variants at this specific residue was identified.
PM2	Met	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 gnomad_v4
PM5	N/A	No pathogenic missense variant at amino acid residue Gly113 has been established in CDKN2B to serve as a comparator. Automated PM5 candidate harvesting found zero same-residue candidates.	pm5_candidates
PM6	Not assessed	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	Not assessed	No family studies demonstrating cosegregation of NM_004936.3:c.338G>A with a CDKN2B-associated phenotype across multiple affected relatives were identified.
PP2	Not assessed	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. Without a demonstrated low benign missense rate, PP2 cannot be applied.
PP3	Not met	Computational evidence does not support a deleterious effect. REVEL score (0.484) falls below the commonly used pathogenic threshold of 0.5. BayesDel score (−0.094) predicts a benign effect. SpliceAI (max delta = 0.00) predicts no splicing alteration. Multiple lines of computational evidence do not converge on a damaging prediction.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for this assessment. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar with no submitter interpretations.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 (6.23×10⁻⁷) is far below the 1% threshold for BA1. BA1 is not met.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 (6.23×10⁻⁷) is far below the 0.3% threshold for BS1. BS1 is not met.	gnomad_v4
BS2	Not met	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. BS2 is not met.	gnomad_v4
BS3	Not assessed	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	Not assessed	No family segregation data are available to assess whether this variant fails to segregate with a CDKN2B-associated phenotype in affected family members.
BP1	Not met	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. The gene is not limited to a truncating-only disease mechanism, so BP1 does not apply.
BP2	Not assessed	No evidence of this variant observed in trans with a pathogenic CDKN2B variant for a fully penetrant dominant disorder was identified.
BP4	Met	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 revel spliceai
BP5	Not assessed	No evidence of this variant found in a case with an alternate molecular basis for disease was identified.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar with no submitter interpretations.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_004936.3:c.338G>A is a missense variant (p.Gly113Asp), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CDKN2B is not a known cause of a recessive cancer predisposition syndrome.
PM4	N/A	PM4 applies to protein length-altering variants (in-frame indels, stop-loss). This variant is a missense substitution, not a length-altering variant.

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