This variant is essentially absent from population databases, with a single heterozygous observation in gnomAD v4.1 (1/1,613,826 alleles; AF = 6.2×10⁻⁷) and no observations in gnomAD v2.1 or gnomAD-Canada, satisfying PM2 at supporting strength.1 No pathogenic or benign classifications exist in ClinVar. No functional studies, segregation data, de novo observations, or variant-specific publications are available. In silico predictors are conflicting (REVEL 0.638 suggesting possible deleterious effect; BayesDel 0.209 in benign range; SpliceAI delta 0.01).2 With only one supporting pathogenic criterion (PM2_supporting) met and no benign criteria met, the variant does not reach the threshold for likely pathogenic, likely benign, or benign classification under generic ACMG/AMP 2015 combination rules. The variant is classified as a Variant of Uncertain Significance (VUS).3
CDK6
Final classification
VUS
PM2
CDK6
c.401A>G
p.Asp134Gly
This variant
This variant is essentially absent from population databases, with a single heterozygous observation in gnomAD v4.1 (1/1,613,826 alleles; AF = 6.2×10⁻⁷) and no observations in gnomAD v2.1 or gnomAD-Canada, satisfying 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; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
CDK6 c.401A>G
PM2
→
VUS
2
clinvar ↗oncokb ↗revelbayesdelspliceai ↗
3
generic_acmg_combination_rules
Gene diagram
· NM_001259.8 · variants mapped to exon structure
CDK6
NM_001259.8
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is essentially absent from population databases. It is absent from gnomAD v2.1, absent from gnomAD-Canada v1.0, and present at extremely low frequency in gnomAD v4.1 (1/1,613,826 alleles; AF = 6.2×10⁻⁷), with the sole observation in the Finnish subpopulation (1/64,022; AF = 1.56×10⁻⁵). All frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment.
Absent from gnomAD v2.1.Absent from gnomAD-Canada v1.0.gnomAD v4.1: 1/1
Assessed · not applied
· 21 not met · 0 not assessed
Pathogenic
PS1
No pathogenic variant at the same amino acid position (Asp134) with the same amino acid change has been identified in ClinVar or the literature.
PS2
No de novo observation with confirmed maternity and paternity is available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect are available for this variant.
PS4
No case-control or cohort data comparing variant prevalence in affected versus unaffected individuals is available.
PM1
The variant does not lie in a statistically significant mutational hotspot (CancerHotspots.org).
PM6
No de novo observation without paternity/maternity confirmation is available for this variant.
PP1
No cosegregation data in affected families is available for this variant.
PP2
While CDK6 has a supported loss-of-function disease mechanism per targeted germline literature review, no missense constraint metric (e.g., missense Z-score, missense pLI) is available to demonstrate a low rate of benign missense variation.
PP3
Multiple lines of computational evidence do not consistently support a deleterious effect.
PP4
No patient phenotype or family history data is available to assess phenotypic specificity for CDK6-related disease.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
The variant's allele frequency is far below the BA1 threshold.
BS1
The variant's allele frequency is far below the BS1 threshold.
BS2
Only a single heterozygous observation exists in gnomAD v4.1 (1 allele out of 1,613,826).
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4
No segregation data demonstrating lack of cosegregation with disease is available for this variant.
BP1
While CDK6 loss of function may be associated with disease per targeted germline literature review, there is no established evidence that CDK6-related disease is caused primarily by truncating variants such that missense variants are expected to be benign.
BP2
No data on observations of this variant in trans with a pathogenic variant (for dominant disorders) or in cis with a pathogenic variant is available.
BP4
Multiple lines of computational evidence do not consistently suggest no impact on gene or gene product.
BP5
No data is available indicating this variant is found in a case with an alternate molecular basis for disease.
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= 6.19645e-07; MAF= 0.00006%, 1/1613826 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56196e-05; MAF= 0.00156%, 1/64022 alleles, homozygotes = 0).
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
6.2e-05%
· 1 / 1,613,826
0 hom
0 hom
European (Finnish) 1 / 64,022 |
0.0016% |
+ 9 not observed (Remaining individuals, Admixed American, 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 = 0.01). REVEL score = 0.638. BayesDel score = 0.208709.
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. CDK6, an intracellular kinase, is amplified 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