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CDK6c.401A>GUncertain significance
Print report
Variant interpretation report

CDK6 c.401A>G, p.(Asp134Gly)

NM_001259.8:c.401A>G NP_001250.1:p.(Asp134Gly) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CDK6

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 22 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 1

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD-Canada v1.0.
  • gnomAD v4.1: 1/1
  • 613
  • 826 alleles (AF = 6.2e-07)
  • Finnish subpopulation: 1/64
  • 022 (AF = 1.56e-05).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 22 · evaluated, threshold not reached

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. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no pathogenic comparator at Asp134 exists.
Still missing
  • No ClinVar or literature entries for any variant at CDK6 residue Asp134.
Sources
clinvar ↗
PS2 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. Details ▾Hide ▴
Still missing
  • No de novo data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB reports no variant-specific functional evidence (Unknown Oncogenic Effect).
Still missing
  • No functional studies available for CDK6 p.Asp134Gly.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Single allele in gnomAD v4.1
  • no case-control studies exist.
Still missing
  • No case-control or cohort data available.
Sources
gnomad_v4 ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • CancerHotspots.org: no significant hotspot at Asp134. Protein kinase domain location alone insufficient for PM1 without supporting constraint data.
Still missing
  • Domain-level constraint metrics for CDK6 kinase domain not available.
PM6 No de novo observation without paternity/maternity confirmation is available for this variant. No publications report de novo occurrence of CDK6 c.401A>G. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No cosegregation data in affected families is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
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. HCI prior probability is not available for CDK6. Details ▾Hide ▴
Evidence considered
  • No missense constraint metrics available for CDK6. HCI prior not supported.
Still missing
  • CDK6 missense constraint data (Z-score
  • regional constraint) not available.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.638 (moderate deleterious signal).
  • BayesDel: 0.209 (benign range).
  • SpliceAI: max delta 0.01 (no predicted splicing impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data is available to assess phenotypic specificity for CDK6-related disease. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no pathogenic classification from any source.
Still missing
  • No authoritative pathogenic classification exists.
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Maximum population AF: 1.56e-05 (Finnish
  • gnomAD v4.1)
  • far below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Overall AF: 6.2e-07 (gnomAD v4.1)
  • far below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Single heterozygous allele in gnomAD v4.1
  • 0 homozygotes. Insufficient for BS2.
Sources
gnomad_v4 ↗
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional studies exist for CDK6 p.Asp134Gly.
BS4 No segregation data demonstrating lack of cosegregation with disease is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
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. The available literature supports a general LoF mechanism but does not specify a truncating-predominant mutational spectrum. Details ▾Hide ▴
Evidence considered
  • CDK6 LoF mechanism supported in literature but not established as truncating-predominant
  • BP1 requires primarily truncating disease mechanism.
Still missing
  • No established CDK6 mutational spectrum demonstrating truncating predominance.
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. Details ▾Hide ▴
Still missing
  • No phase data available for this variant.
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.638 (suggests possible deleterious effect
  • not uniformly benign).
  • BayesDel: 0.209 (benign range).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP5 No data is available indicating this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no benign classification from any source.
Still missing
  • No authoritative benign classification exists.
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar; no submitter classification exists. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no classification from any source.
Still missing
  • No authoritative classification exists.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 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). Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Asp134Gly) does not qualify for PVS1 null-variant assessment.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes (stop-loss, in-frame insertions/deletions); this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic missense comparator exists at Asp134.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions only; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants without predicted splice impact. NM_001259.8:c.401A>G is a missense variant (p.Asp134Gly). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CDK6
Transcript
NM_001259.8
Coding (HGVS c.)
NM_001259.8:c.401A>G
Protein (HGVS p.)
NP_001250.1:p.(Asp134Gly)
GRCh38
chr7:92725762 T>C
GRCh37
chr7:92355076 T>C

Gene diagram

Every interpreted variant in CDK6, mapped onto the exon structure of NM_001259.8. Select a row to find it on the plot.

CDK6NM_001259.8
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,826 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,826 alleles · 0 hom
European (Finnish)1 / 64,022 1.6e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +16 bp
0.010
SpliceAI acceptor gainat -459 bp
0.000
SpliceAI donor lossat -136 bp
0.000
SpliceAI donor gainat +31 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.638
BayesDel
0.209

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.638 (moderate deleterious signal).
  • BayesDel: 0.209 (benign range).
  • SpliceAI: max delta 0.01 (no predicted splicing impact).
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.638 (suggests possible deleterious effect
  • not uniformly benign).
  • BayesDel: 0.209 (benign range).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants without predicted splice impact. NM_001259.8:c.401A>G is a missense variant (p.Asp134Gly). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.638. BayesDel score = 0.208709.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,826 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.