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CDKN2Bc.338G>AUncertain significance
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Variant interpretation report

CDKN2B c.338G>A, p.(Gly113Asp)

NM_004936.3:c.338G>A NP_004927.2:p.(Gly113Asp) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CDKN2B

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 1/1
  • 606
  • 290 alleles
  • AF=6.23×10⁻⁷
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: −0.094 (benign)
  • REVEL: 0.484 (below 0.5 pathogenic threshold)
  • SpliceAI: max delta = 0.00 (no splicing impact)
Sources
bayesdelrevelspliceai ↗

Not met · 9 · evaluated, threshold not reached

PS4 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar with zero submitters
  • No published case-control or cohort enrichment data
Still missing
  • No case-control data for CDKN2B c.338G>A
  • No cohort prevalence data in affected individuals
Sources
clinvar ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.484 (below 0.5 pathogenic threshold)
  • BayesDel: −0.094 (benign-leaning)
  • SpliceAI: max delta = 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
PP5 No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar with no submitter interpretations. Details ▾Hide ▴
Evidence considered
  • ClinVar contains zero entries for this variant
Sources
clinvar ↗
BA1 The allele frequency in gnomAD v4.1 (6.23×10⁻⁷) is far below the 1% threshold for BA1. BA1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.23×10⁻⁷
  • well below 1%
Sources
gnomad_v4 ↗
BS1 The allele frequency in gnomAD v4.1 (6.23×10⁻⁷) is far below the 0.3% threshold for BS1. BS1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.23×10⁻⁷
  • well below 0.3%
Sources
gnomad_v4 ↗
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. BS2 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 homozygotes = 0
Still missing
  • No phasing data to assess trans with pathogenic variant
Sources
gnomad_v4 ↗
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. The gene is not limited to a truncating-only disease mechanism, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • CDKN2B is a tumor suppressor with both truncating and missense pathogenic variants described
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar with no submitter interpretations. Details ▾Hide ▴
Evidence considered
  • ClinVar contains zero entries for this variant
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no diagnostic laboratory has submitted a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
  • ClinVar contains zero entries for this variant
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS1 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. Details ▾Hide ▴
Evidence considered
  • ClinVar absent for CDKN2B c.338G>A and any variant at residue Gly113
Still missing
  • No established pathogenic variant at Gly113 in CDKN2B
Sources
clinvar ↗
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. Details ▾Hide ▴
Still missing
  • No reported de novo event with confirmed parentage for this variant
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. Details ▾Hide ▴
Still missing
  • No functional assay data for CDKN2B p.Gly113Asp
  • MaveDB and published functional studies do not include this variant
PM1 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. Details ▾Hide ▴
Evidence considered
  • Residue 113 is in the second ankyrin repeat domain (Ank 2)
  • No hotspot or mutation clustering data for residue 113
Still missing
  • No CDKN2B-specific mutational hotspot data for residue Gly113
  • Domain-level constraint metrics (e.g.
  • missense Z-score for the ankyrin repeat domain) not available
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. Details ▾Hide ▴
Still missing
  • No reported de novo event for this variant
PP1 No family studies demonstrating cosegregation of NM_004936.3:c.338G>A with a CDKN2B-associated phenotype across multiple affected relatives were identified. Details ▾Hide ▴
Still missing
  • No cosegregation data available
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. Without a demonstrated low benign missense rate, PP2 cannot be applied. Details ▾Hide ▴
Still missing
  • No CDKN2B missense constraint metric (Z-score) available
  • Gene-level benign missense variation rate not established
PP4 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. Details ▾Hide ▴
Still missing
  • No clinical phenotype or family history provided
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. Details ▾Hide ▴
Still missing
  • No functional assay data for CDKN2B p.Gly113Asp
BS4 No family segregation data are available to assess whether this variant fails to segregate with a CDKN2B-associated phenotype in affected family members. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No evidence of this variant observed in trans with a pathogenic CDKN2B variant for a fully penetrant dominant disorder was identified. Details ▾Hide ▴
Still missing
  • No phasing or co-occurrence data with other CDKN2B variants
BP5 No evidence of this variant found in a case with an alternate molecular basis for disease was identified. Details ▾Hide ▴
Still missing
  • No case with alternate molecular diagnosis available
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 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). Details ▾Hide ▴
Evidence considered
  • Missense substitution (c.338G>A
  • p.Gly113Asp)
  • not a null variant
  • Variant bucket: 'other'
  • apply_generic_pvs1_framework: false
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length-altering variants (in-frame indels, stop-loss). This variant is a missense substitution, not a length-altering variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • Zero same-residue pathogenic comparator variants identified
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense (c.338G>A
  • p.Gly113Asp)
  • not synonymous

Identifiers

Gene
CDKN2B
Transcript
NM_004936.3
Coding (HGVS c.)
NM_004936.3:c.338G>A
Protein (HGVS p.)
NP_004927.2:p.(Gly113Asp)
GRCh38
chr9:22006066 C>T
GRCh37
chr9:22006065 C>T

Gene diagram

Every interpreted variant in CDKN2B, mapped onto the exon structure of NM_004936.3. Select a row to find it on the plot.

CDKN2BNM_004936.3
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,606,290 alleles AF 6.23e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,606,290 alleles · 0 hom
Remaining individuals1 / 62,372 1.6e-05
0 alternate alleles recorded in 9 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.030

Other predictors

REVEL
0.484
BayesDel
-0.094

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: −0.094 (benign)
  • REVEL: 0.484 (below 0.5 pathogenic threshold)
  • SpliceAI: max delta = 0.00 (no splicing impact)
Sources
bayesdelrevelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.484 (below 0.5 pathogenic threshold)
  • BayesDel: −0.094 (benign-leaning)
  • SpliceAI: max delta = 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense (c.338G>A
  • p.Gly113Asp)
  • not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.484. BayesDel score = -0.0936784.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,606,290 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.