NM_001259.8:c.334G>A (p.Val112Ile) in CDK6 is a missense variant absent from ClinVar and observed at ultra-rare frequency in gnomAD (AF=4.97e-6 in v4.1, 2-8 total alleles across datasets).1 PM2 (supporting) is met: the variant is present at extremely low frequency across gnomAD populations (highest subpopulation AF=6.70e-5), well below the 0.1% threshold.2 BP4 (supporting benign) is met: multiple independent computational predictors — REVEL (0.114), BayesDel (-0.467), and SpliceAI (0.00) — concur that the variant is likely neutral with no predicted impact on splicing or protein function.3 PVS1 is not applicable: this is a missense variant, not a null variant, and does not meet the ClinGen SVI PVS1 criteria (PMC6185798).4 No functional data (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), case-control data (PS4), or ClinVar classifications (PS5/PP5/BP6) are available for this variant. With PM2 (supporting pathogenic) and BP4 (supporting benign), the evidence is balanced and insufficient to classify beyond a Variant of Uncertain Significance per ACMG/AMP 2015 framework.5
CDK6
Final classification
VUS
CDK6 c.334G>A · p.Val112Ile
CDK6
NM_001259.8:c.334G>A (p.Val112Ile) in CDK6 is a missense variant absent from ClinVar and observed at ultra-rare frequency in gnomAD (AF=4.97e-6 in v4.1, 2-8 total alleles across datasets).
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.334G>A
PM2 + BP4
→
VUS
3
revelbayesdelspliceai ↗
5
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 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
PM2 applies when a variant is absent from or observed at extremely low frequency in large population databases. This variant is present in gnomAD v2.1 at AF=7.20e-6 (2/277,844 alleles) and in gnomAD v4.1 at AF=4.97e-6 (8/1,609,906 alleles), with no homozygotes. The highest observed population frequency is 6.70e-5 (African/African American, gnomAD v4.1), well below the 0.1% threshold. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: AF=7.20e-6 (2/277844)0 homozygotes
✓
BP4
supporting
Benign
BP4 applies when multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.114 (below the typical 0.5 deleterious threshold), BayesDel score is -0.467 (negative, predicting a benign/neutral effect), and SpliceAI max delta score is 0.00 (no predicted splice impact). Three independent computational predictors concur that this variant is likely benign.
REVEL: 0.114 (benign range)BayesDel: -0.467 (benign range)SpliceAI: max delta score 0.00 (no splice impact)
Assessed · not applied
Pathogenic
PS2
PS2 requires a confirmed de novo observation with both parental samples tested.
PS3
PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect.
PS4
PS4 requires a significantly increased prevalence of the variant in affected individuals compared to controls.
PM1
PM1 requires the variant to be located in a mutational hotspot and/or critical and well-established functional domain without benign variation.
PM6
PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1
PP1 requires co-segregation with disease in multiple affected family members.
PP2
PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect.
PP4
PP4 requires the variant to be found in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source to have classified the variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in any general population.
BS1
BS1 requires an allele frequency >0.3% in any population.
BS2
BS2 requires observation of the variant in a homozygous state, in trans with a pathogenic variant, or in cis with a pathogenic variant in a healthy individual.
BS3
BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing.
BS4
BS4 requires lack of segregation with disease in multiple affected family members.
BP1
BP1 applies to missense variants in genes where only truncating variants are known to cause disease.
BP2
BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to have classified the variant as benign.
N/A · 4
PVS1 · PS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.96923e-06; MAF= 0.00050%, 8/1609906 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.69972e-05; MAF= 0.00670%, 5/74630 alleles, homozygotes = 0); grpmax FAF= 2.557e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.19828e-06; MAF= 0.00072%, 2/277844 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.04629e-05; MAF= 0.00405%, 1/24714 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,609,906
0 hom · FAF 0.0026%
0 hom · FAF 0.0026%
African/African American 5 / 74,630 |
0.0067% |
Remaining individuals 2 / 62,326 |
0.0032% |
Admixed American 1 / 59,096 |
0.0017% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.00072%
· 2 / 277,844
0 hom
0 hom
African/African American 1 / 24,714 |
0.004% |
Admixed American 1 / 33,754 |
0.003% |
+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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 = 0.00). REVEL score = 0.114. BayesDel score = -0.467347.
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