NM_001259.8:c.915G>T (p.Arg305Ser) in CDK6 is a missense variant observed at extremely low frequency in population databases (gnomAD v2.1 AF=0.0016%, v4.1 AF=0.00025%), meeting PM2 at supporting level.1 Multiple in silico tools predict a benign effect: REVEL score 0.126, BayesDel score -0.39903, and SpliceAI max delta 0.02. These concordant predictions meet BP4 at supporting benign level.2 The variant is absent from ClinVar, COSMIC, and the published literature. No functional, segregation, or case-control data are available. No pathogenic comparator exists at residue Arg305.3 With one supporting criterion for pathogenicity (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify this variant as either pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.4
CDK6
Final classification
VUS
CDK6 c.915G>T · p.Arg305Ser
CDK6
NM_001259.8:c.915G>T (p.Arg305Ser) in CDK6 is a missense variant observed at extremely low frequency in population databases (gnomAD v2.1 AF=0.0016%, v4.1 AF=0.00025%), meeting PM2 at supporting level.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDK6 c.915G>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
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 · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.47815e-06; MAF= 0.00025%, 4/1614108 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.45613e-05; MAF= 0.00446%, 2/44882 alleles, homozygotes = 0); grpmax FAF= 7.39e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.60471e-05; MAF= 0.00160%, 4/249266 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000163097; MAF= 0.01631%, 3/18394 alleles, homozygotes = 0); grpmax FAF= 4.412e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,614,108
0 hom · FAF 0.00074%
0 hom · FAF 0.00074%
East Asian 2 / 44,882 |
0.0045% |
Remaining individuals 1 / 62,510 |
0.0016% |
South Asian 1 / 91,076 |
0.0011% |
+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0016%
· 4 / 249,266
0 hom · FAF 0.0044%
0 hom · FAF 0.0044%
East Asian 3 / 18,394 |
0.016% |
South Asian 1 / 30,614 |
0.0033% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
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 = 0.02). REVEL score = 0.126. BayesDel score = -0.39903.
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