About CDK6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK6 c.915G>T, p.(Arg305Ser)
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
This variant is extremely rare in population databases. In gnomAD v2.1 it is observed at an allele frequency of 0.0016% (4/249,266 alleles, no homozygotes; grpmax FAF 4.41e-05). In gnomAD v4.1 it is observed at 0.00025% (4/1,614,108 alleles). It is absent from gnomAD-Canada. These frequencies are well below the PM2 threshold of 0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.126 (below pathogenic threshold), BayesDel score is -0.39903 (strongly predicting benign), and SpliceAI predicts no splicing alteration (max delta 0.02). Three independent in silico tools are concordant in predicting a benign or non-damaging effect.
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
4 / 1,614,108 alleles
gnomAD v4.1: 4 / 1,614,108 alleles. Recorded AF 2.47815e-06. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 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.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.
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.
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v2.1 it is observed at an allele frequency of 0.0016% (4/249,266 alleles, no homozygotes; grpmax FAF 4.41e-05). In gnomAD v4.1 it is observed at 0.00025% (4/1,614,108 alleles). It is absent from gnomAD-Canada. These frequencies are well below the PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=1.60e-05 (4/249
- 266 alleles
- 0 homozygotes)
- grpmax FAF=4.41e-05
- gnomAD v4.1: AF=2.48e-06 (4/1
- 614
- 108 alleles
- grpmax FAF=7.39e-06
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.126 (below pathogenic threshold), BayesDel score is -0.39903 (strongly predicting benign), and SpliceAI predicts no splicing alteration (max delta 0.02). Three independent in silico tools are concordant in predicting a benign or non-damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.126 (below deleterious threshold)
- BayesDel: -0.39903 (benign prediction)
- SpliceAI: max delta 0.02 (no predicted splice impact)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No previously established pathogenic missense variant at the same amino acid residue (Arg305) has been identified in ClinVar or the published literature. There is no basis to apply PS1. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar. No pathogenic comparator at Arg305 could be identified.
Still missing
- No pathogenic variant at Arg305 in CDK6 in any public database.
Sources
PS2 No de novo occurrence data with confirmed paternity and maternity are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No family or de novo testing data.
PS3 No well-established in vitro or in vivo functional studies have been reported for this variant. OncoKB classifies it as Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No variant-specific functional studies found in literature.
Still missing
- No functional characterization of CDK6 p.Arg305Ser.
Sources
PS4 No case-control or cohort data demonstrate a significantly increased prevalence of this variant in affected individuals compared to controls. Details ▾Hide ▴
Evidence considered
- No case-control association data available.
Still missing
- No prevalence data in affected populations.
PM1 Residue Arg305 in CDK6 is not located in a statistically significant mutational hotspot, nor is it in a well-established critical functional domain lacking benign variation. The hotspot screen is negative. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: Arg305 is not a significant hotspot residue.
PM5 No pathogenic missense variant has been reported at the same amino acid residue (Arg305) in CDK6. The automated PM5 candidate search found zero same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue pathogenic comparator variants at Arg305 in CDK6.
Still missing
- No pathogenic comparator at Arg305.
Sources
pm5_candidates
PM6 No de novo occurrence data (assumed or confirmed) are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No de novo testing data.
PP1 No co-segregation data in affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation or family data available.
Still missing
- No family or segregation data.
PP2 CDK6 does not have an established gene-level constraint profile showing a low rate of benign missense variation in a germline disease context. The HCI prior is unavailable for CDK6, and no ClinGen-curated missense constraint data exist. Details ▾Hide ▴
Evidence considered
- HCI prior not available for CDK6. No gene-level missense constraint data in a germline disease context.
Still missing
- No gene-level missense constraint metrics (z-score
- missense depletion) available for CDK6.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.126 (well below the 0.5 pathogenic threshold), BayesDel score is -0.39903 (predicting benign), and SpliceAI predicts no splicing impact (max delta 0.02). These do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.126 (below pathogenic threshold)
- BayesDel: -0.39903 (benign prediction)
- SpliceAI: max delta 0.02 (no splice impact)
Sources
PP4 No patient phenotype or family history data are available to assess specificity for a CDK6-associated disorder. Details ▾Hide ▴
Evidence considered
- No patient phenotype information available.
Still missing
- No phenotype or clinical indication data.
PP5 No reputable source (ClinVar, clinical laboratory, or published report) has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable source classification available.
Sources
BA1 The allele frequency in gnomAD (0.0016% in v2.1, 0.00025% in v4.1) is far below the BA1 threshold of 1%. Details ▾Hide ▴
BS1 The allele frequency in gnomAD (0.0016% in v2.1, 0.00025% in v4.1) is far below the BS1 threshold of 0.3%. Details ▾Hide ▴
BS2 No data available on observation of this variant in healthy adults where full penetrance of a CDK6-associated disorder would be expected at an early age. Details ▾Hide ▴
Evidence considered
- No healthy-adult carrier data available.
Still missing
- No population-level phenotype data for carriers.
BS3 No well-established in vitro or in vivo functional studies demonstrate that this variant has no deleterious effect on protein function. Details ▾Hide ▴
Evidence considered
- No functional studies have characterized CDK6 p.Arg305Ser.
Still missing
- No functional characterization of this variant.
Sources
BS4 No segregation data in affected families are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No family or segregation data available.
Still missing
- No segregation data.
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. CDK6 lacks a well-established germline disease association limited to truncating variants; the available literature does not demonstrate that CDK6 germline disease is caused exclusively or primarily by loss-of-function truncations. Details ▾Hide ▴
Evidence considered
- CDK6 germline disease context is not sufficiently established to assert that only truncating variants cause disease.
Still missing
- No ClinGen-curated gene-disease validity for CDK6 with a truncating-only mechanism.
BP2 BP2 applies to missense variants in genes where only missense variants cause disease. CDK6 does not meet this criterion; loss-of-function mechanism is also supported. Details ▾Hide ▴
Evidence considered
- CDK6 is not a gene where only missense variants cause disease.
BP5 No case has been reported in which this variant is observed in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate-molecular-basis data available.
Still missing
- No co-occurrence data with another pathogenic variant.
BP6 No reputable source (ClinVar, clinical laboratory) has classified this variant as benign. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable benign classification available.
Sources
PS5 This variant does not lie in a statistically significant mutational hotspot, and no established pathogenic variant shares the same amino acid change (see PS1). The residue is not in a well-characterized functional domain with prior pathogenic variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue Arg305 is not a statistically significant hotspot.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Arg305Ser); it does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- NM_001259.8:c.915G>T is a missense substitution
- not a null variant eligible for PVS1.
Sources
PM3 N/ACDK6 is not established as a recessive disease gene. No data for this variant detected in trans with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is a missense substitution, not a non-repeat in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AThis is a missense substitution, not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (p.Arg305Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CDK6
- Transcript
- NM_001259.8
- Coding (HGVS c.)
- NM_001259.8:c.915G>T
- Protein (HGVS p.)
- NP_001250.1:p.(Arg305Ser)
- GRCh38
- chr7:92615206 C>A
- GRCh37
- chr7:92244520 C>A
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
4 / 1,614,108 alleles
AF 2.48e-06 · 0 homozygotes · FAF 7.39e-06
gnomAD v2.1
4 / 249,266 alleles
AF 1.6e-05 · 0 homozygotes · FAF 4.41e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,614,108 alleles · 0 hom · FAF 7.4e-06
| East Asian2 / 44,882 | 4.5e-05 |
| Remaining individuals1 / 62,510 | 1.6e-05 |
| South Asian1 / 91,076 | 1.1e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 1.6e-05 · 4 / 249,266 alleles · 0 hom · FAF 4.4e-05
| East Asian3 / 18,394 | 0.00016 |
| South Asian1 / 30,614 | 3.3e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.126
- BayesDel
- -0.399
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.126 (below pathogenic threshold), BayesDel score is -0.39903 (strongly predicting benign), and SpliceAI predicts no splicing alteration (max delta 0.02). Three independent in silico tools are concordant in predicting a benign or non-damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.126 (below deleterious threshold)
- BayesDel: -0.39903 (benign prediction)
- SpliceAI: max delta 0.02 (no predicted splice impact)
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.126 (well below the 0.5 pathogenic threshold), BayesDel score is -0.39903 (predicting benign), and SpliceAI predicts no splicing impact (max delta 0.02). These do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.126 (below pathogenic threshold)
- BayesDel: -0.39903 (benign prediction)
- SpliceAI: max delta 0.02 (no splice impact)
Sources
BP7 N/AThis is a missense variant (p.Arg305Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.126. BayesDel score = -0.39903.
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
4 / 1,614,108 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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.915G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-92244520-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-92615206-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-92615206-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001259.8%3Ac.915G…
- OncoKB ↗www.oncokb.org/gene/CDK6/R305S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK6+c.915G%3ET
- 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= 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.
gnomAD 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.
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 = 0.02). REVEL score = 0.126. BayesDel score = -0.39903.
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.