About CDK6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK6 c.334G>A, p.(Val112Ile)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,609,906 alleles
gnomAD v4.1: 8 / 1,609,906 alleles. Recorded AF 4.96923e-06. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
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.
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.
PVS1 is not applicable: this is a missense variant, not a null variant, and does not meet the ClinGen SVI PVS1 criteria (PMC6185798).
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.
No criteria match.
Met · 2
PM2 SupportingPM2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=7.20e-6 (2/277
- 844)
- 0 homozygotes
- gnomAD v4.1: AF=4.97e-6 (8/1
- 609
- 906)
- Highest subpopulation AF: 6.70e-5 (African/African American
- gnomAD v4.1)
- Absent from gnomAD-Canada v1.0
Sources
BP4 SupportingBP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.114 (benign range)
- BayesDel: -0.467 (benign range)
- SpliceAI: max delta score 0.00 (no splice impact)
Sources
Not met · 20 · evaluated, threshold not reached
PS2 PS2 requires a confirmed de novo observation with both parental samples tested. No de novo data is available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data in any available source
Still missing
- No parental or family studies performed
PS3 PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No functional data exists for NM_001259.8:c.334G>A. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No publications mention this variant. In silico predictions alone (REVEL 0.114, BayesDel -0.467) are not a substitute for experimental functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies found in literature
Still missing
- No experimental functional studies available for this variant
Sources
PS4 PS4 requires a significantly increased prevalence of the variant in affected individuals compared to controls. No case-control data or cohort prevalence data is available for this variant. Details ▾Hide ▴
Evidence considered
- No case-control or cohort prevalence data available
Still missing
- No affected individual cohort data
PM1 PM1 requires the variant to be located in a mutational hotspot and/or critical and well-established functional domain without benign variation. Cancerhotspots.org does not identify residue 112 as a statistically significant hotspot. No literature was identified that characterizes position Val112 as a critical functional domain. Without domain-level evidence or a known hotspot, PM1 is not met. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- no literature characterizing Val112 as a critical domain
Still missing
- No domain characterization for CDK6 residue 112
PM6 PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo data is available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data in any available source
Still missing
- No parental or family studies performed
PP1 PP1 requires co-segregation with disease in multiple affected family members. No segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies available
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. While CDK6 is implicated in cancer through somatic alterations, no germline disease mechanism with missense variants as the primary mechanism has been established. Gene-level constraint metrics are not available to support a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- CDK6 lacks established germline disease association with missense variants as primary mechanism
Still missing
- No gene constraint data or established germline missense disease mechanism
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.114 (below the 0.5 threshold typically used for deleterious prediction), BayesDel score is -0.467 (negative score predicts benign), and SpliceAI max delta is 0.00 (no predicted splice impact). All three in silico predictors favor a benign or neutral effect; no lines of computational evidence support pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.114 (benign range)
- BayesDel: -0.467 (benign range)
- SpliceAI: max delta score 0.00 (no splice impact)
Sources
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. No phenotype or family history data is available for this case. Details ▾Hide ▴
Evidence considered
- No patient phenotype or family history data available
Still missing
- No patient phenotype or clinical context provided
PP5 PP5 requires a reputable source to have classified the variant as pathogenic. This variant is absent from ClinVar and has not been reported by any submitter. No 3-star expert panel classification exists for this variant. Details ▾Hide ▴
BA1 BA1 requires an allele frequency >1% in any general population. The highest observed population frequency is 6.70e-5 (0.0067%) in the African/African American population (gnomAD v4.1), which is well below the 1% threshold. Details ▾Hide ▴
Evidence considered
- Highest population AF: 6.70e-5 (0.0067%)
- far below 1% threshold
Sources
BS1 BS1 requires an allele frequency >0.3% in any population. The highest observed population frequency is 6.70e-5 (0.0067%) in the African/African American population (gnomAD v4.1), which is well below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- Highest population AF: 6.70e-5 (0.0067%)
- far below 0.3% threshold
Sources
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. No homozygotes are observed in gnomAD, and no data regarding trans or cis configuration with pathogenic variants is available. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD
- no trans/cis data available
Still missing
- No phase information with pathogenic variants
Sources
BS3 BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No experimental functional studies exist for this variant. In silico predictions (REVEL 0.114, BayesDel -0.467) suggest a benign effect but are not a substitute for well-established functional studies. Details ▾Hide ▴
Evidence considered
- No experimental functional studies available for this variant
- In silico predictions suggest benign effect but do not meet BS3 evidentiary standard
Still missing
- No well-established functional studies for this variant
BS4 BS4 requires lack of segregation with disease in multiple affected family members. No segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies available
BP1 BP1 applies to missense variants in genes where only truncating variants are known to cause disease. CDK6 is primarily associated with somatic alterations in cancer; the germline disease mechanism is not well-characterized with either a truncating-only or missense-inclusive pattern. This criterion does not apply in the absence of an established germline truncating-only disease mechanism. Details ▾Hide ▴
Evidence considered
- CDK6 lacks an established germline disease mechanism with truncating-only etiology
Still missing
- No established germline disease mechanism for CDK6
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. No such data is available. Details ▾Hide ▴
Evidence considered
- No trans or cis configuration data available
Still missing
- No phase information with pathogenic variants
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data is available for this case. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No clinical testing for alternate genetic etiology
BP6 BP6 requires a reputable source to have classified the variant as benign. This variant is absent from ClinVar and has not been classified by any submitter. No 3-star expert panel classification exists for this variant. Details ▾Hide ▴
PS5 PS5 requires a reputable source to have classified the variant as pathogenic. This variant is absent from ClinVar and has not been reported as pathogenic by any submitted source. Details ▾Hide ▴
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to this missense variant (NM_001259.8:c.334G>A; p.Val112Ile). The variant does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution c.334G>A in exon 3
- producing p.Val112Ile
- not a null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires a different nucleotide change at the same codon producing an identical amino acid change that has been established as pathogenic. No known pathogenic variant at codon 112 of CDK6 has been identified in ClinVar or the literature, and no alternative nucleotide change resulting in V112I has been reported as pathogenic. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator variant at codon 112 of CDK6
Sources
clinvar ↗pm5_candidates
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid position. No pathogenic or likely pathogenic comparator variants at codon 112 of CDK6 were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator variants identified in ClinVar
Sources
pm5_candidatesclinvar ↗
BP7 N/ABP7 applies only to synonymous variants with no predicted splice impact. NM_001259.8:c.334G>A is a missense variant (p.Val112Ile) and does not qualify for BP7 assessment. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Val112Ile)
- not synonymous
Identifiers
- Gene
- CDK6
- Transcript
- NM_001259.8
- Coding (HGVS c.)
- NM_001259.8:c.334G>A
- Protein (HGVS p.)
- NP_001250.1:p.(Val112Ile)
- GRCh38
- chr7:92774731 C>T
- GRCh37
- chr7:92404045 C>T
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDK6
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
8 / 1,609,906 alleles
AF 4.97e-06 · 0 homozygotes · FAF 2.56e-05
gnomAD v2.1
2 / 277,844 alleles
AF 7.2e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,609,906 alleles · 0 hom · FAF 2.6e-05
| African/African American5 / 74,630 | 6.7e-05 |
| Remaining individuals2 / 62,326 | 3.2e-05 |
| Admixed American1 / 59,096 | 1.7e-05 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 7.2e-06 · 2 / 277,844 alleles · 0 hom
| African/African American1 / 24,714 | 4e-05 |
| Admixed American1 / 33,754 | 3e-05 |
0 alternate alleles recorded in 6 other groups: Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.114
- BayesDel
- -0.467
How the predictions were used
BP4 SupportingBP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.114 (benign range)
- BayesDel: -0.467 (benign range)
- SpliceAI: max delta score 0.00 (no splice impact)
Sources
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.114 (below the 0.5 threshold typically used for deleterious prediction), BayesDel score is -0.467 (negative score predicts benign), and SpliceAI max delta is 0.00 (no predicted splice impact). All three in silico predictors favor a benign or neutral effect; no lines of computational evidence support pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.114 (benign range)
- BayesDel: -0.467 (benign range)
- SpliceAI: max delta score 0.00 (no splice impact)
Sources
BP7 N/ABP7 applies only to synonymous variants with no predicted splice impact. NM_001259.8:c.334G>A is a missense variant (p.Val112Ile) and does not qualify for BP7 assessment. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Val112Ile)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.114. BayesDel score = -0.467347.
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
8 / 1,609,906 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001259.8%3Ac.334G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-92404045-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-92774731-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-92774731-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001259.8%3Ac.334G…
- OncoKB ↗www.oncokb.org/gene/CDK6/V112I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK6+c.334G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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= 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.
gnomAD 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).
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 = 0.00). REVEL score = 0.114. BayesDel score = -0.467347.
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.