NM_001259.8:c.401A>G

CDK6 · NP_001250.1:p.(Asp134Gly) · NM_001259.8

GRCh37: chr7:92355076 T>C · GRCh38: chr7:92725762 T>C

Gene: CDK6 Transcript: NM_001259.8

Final call

VUS

PM2 supporting

Variant details

Gene

CDK6

Transcript

NM_001259.8

Protein

NP_001250.1:p.(Asp134Gly)

gnomAD AF

6.196454884231634e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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).

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).

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
BP3	N/A	BP3 applies to in-frame insertions/deletions only; this is a missense substitution.
PM3	N/A	PM3 applies to recessive disorders requiring a second pathogenic variant in trans; CDK6 is not established as a recessive disease gene and no second variant data is available.
PM4	N/A	PM4 applies to protein length changes (stop-loss, in-frame insertions/deletions); this is a missense substitution.
PVS1	N/A	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). NM_001259.8:c.401A>G is a missense variant (p.Asp134Gly) and does not fall into any PVS1 decision tree bucket per the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic variant at the same amino acid position (Asp134) with the same amino acid change has been identified in ClinVar or the literature. The variant is absent from ClinVar.	clinvar
PS2	Not met	No de novo observation with confirmed maternity and paternity is available for this variant. No publications report de novo occurrence of CDK6 c.401A>G.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect are available for this variant. OncoKB classifies it as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control or cohort data comparing variant prevalence in affected versus unaffected individuals is available. The variant is observed in only 1 of 1,613,826 alleles in gnomAD v4.1 with no disease-specific prevalence data.	gnomad_v4
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar; no submitter classification exists.	clinvar
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot (CancerHotspots.org). Although residue Asp134 is located within the CDK6 protein kinase domain, there is no domain-specific constraint data demonstrating a critical functional domain with low benign variation sufficient for PM1 application under generic ACMG.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (Asp134) has been identified in ClinVar or the literature. PM5 candidate harvesting returned zero same-residue comparators.	pm5_candidates
PM6	Not met	No de novo observation without paternity/maternity confirmation is available for this variant. No publications report de novo occurrence of CDK6 c.401A>G.
PP1	Not met	No cosegregation data in affected families is available for this variant.
PP2	Not met	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. HCI prior probability is not available for CDK6.
PP3	Not met	Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score is 0.638 (moderate, above 0.5 threshold), but BayesDel score is 0.209 (benign range, below 0.25 threshold), and SpliceAI predicts no splicing impact (max delta = 0.01). The in silico evidence is conflicting rather than uniformly deleterious.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available to assess phenotypic specificity for CDK6-related disease.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The variant's allele frequency is far below the BA1 threshold. The highest observed population frequency is 1.56×10⁻⁵ (Finnish subpopulation, gnomAD v4.1), well below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The variant's allele frequency is far below the BS1 threshold. The overall gnomAD v4.1 frequency is 6.2×10⁻⁷ (1/1,613,826 alleles), far below the 0.3% BS1 threshold for disorders with expected low population prevalence.	gnomad_v4
BS2	Not met	Only a single heterozygous observation exists in gnomAD v4.1 (1 allele out of 1,613,826). This single observation is insufficient to apply BS2, which requires observation in multiple healthy adults for a disorder expected to be fully penetrant at an early age. No homozygous observations exist.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease is available for this variant.
BP1	Not met	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. The available literature supports a general LoF mechanism but does not specify a truncating-predominant mutational spectrum.
BP2	Not met	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	Not met	Multiple lines of computational evidence do not consistently suggest no impact on gene or gene product. REVEL score (0.638) suggests a possible deleterious effect, conflicting with the lower BayesDel score (0.209). Evidence is not uniformly benign.	revel bayesdel spliceai
BP5	Not met	No data is available indicating this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splice impact. NM_001259.8:c.401A>G is a missense variant (p.Asp134Gly).

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.