Starting

Initialising…

CDK2

Final classification

VUS

CDK2 c.665C>T · p.Pro222Leu

CDK2

NM_001798.4:c.665C>T (p.Pro222Leu) in CDK2 is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2 at supporting strength.

Gene

CDK2

Transcript

NM_001798.4

HGVS · transcript:coding

NM_001798.4:c.665C>T

Consequence

N/A

GRCh38

chr12:55971120 C>T

GRCh37

chr12:56364904 C>T

Basis 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; combination = 1 supporting, which maps to VUS. ▾

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; combination = 1 supporting, which maps to VUS.

Classification rationale

PM2 VUS

CDK2 c.665C>T

NM_001798.4:c.665C>T (p.Pro222Leu) in CDK2 is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2 at supporting strength.¹ No other ACMG/AMP criterion was met. The variant lacks ClinVar classification, functional studies, de novo observations, segregation data, hotspot localization, same-residue pathogenic comparators, and conclusive in silico evidence.² With only one supporting criterion (PM2_supporting) and no other criteria met in either the pathogenic or benign direction, this variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules (PMID:25741868).³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 clinvar ↗revelbayesdelspliceai ↗pm5_candidates

3 generic_acmg_combination_rules

Gene diagram · NM_001798.4 · variants mapped to exon structure

CDK2 NM_001798.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.661. BayesDel score = -0.0440517.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots