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CDK4c.322C>TUncertain significance
Print report
Variant interpretation report

CDK4 c.322C>T, p.(Pro108Ser)

NM_000075.3:c.322C>T NP_000066.1:p.(Pro108Ser) 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 CDK4

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: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

This variant is absent from all large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with a combined allele count of zero across all populations. Under generic ACMG/AMP rules, an allele frequency below 0.1% in population databases supports moderate evidence for pathogenicity.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.251 (below the 0.5 pathogenic threshold and within the indeterminate-to-benign range), BayesDel score is -0.25851 (negative, indicating a benign prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). Three independent computational predictors are concordant in suggesting a benign 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 moderate, BP4 supporting benign; combination = 1 moderate + 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.

SpliceAI score
0.010 maximum delta

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

Applied · BP4 → 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. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.

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: 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.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000075.3:c.322C>T (p.Pro108Ser) is a missense variant in CDK4, a gene in which activating missense variants are associated with autosomal dominant familial melanoma.

This variant is absent from all large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting moderate evidence for pathogenicity (PM2).

Multiple lines of computational evidence suggest a benign effect: REVEL score is 0.251 (below the pathogenic threshold), BayesDel score is -0.25851 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.01). This supports BP4 (supporting benign).

No functional studies, case-control data, segregation data, or clinical phenotype information are available for this variant. The variant is absent from ClinVar and has not been reported in the somatic or germline literature.

The variant is a missense substitution at a residue (Pro108) that is not a recognized mutational hotspot and has no comparator pathogenic variants at the same position.

Overall, the only applicable criterion is PM2 (moderate) for absence from population databases, and BP4 (supporting benign) for concordant benign computational predictions. With one moderate pathogenic criterion and one supporting benign criterion, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic, and insufficient evidence exists to classify it as benign. This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 ModerateThis variant is absent from all large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with a combined allele count of zero across all populations. Under generic ACMG/AMP rules, an allele frequency below 0.1% in population databases supports moderate evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AC=0
  • AF=0).
  • Absent from gnomAD v4.1 (AC=0
  • Absent from gnomAD-Canada v1.0 (AC=0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.251 (below the 0.5 pathogenic threshold and within the indeterminate-to-benign range), BayesDel score is -0.25851 (negative, indicating a benign prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). Three independent computational predictors are concordant in suggesting a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.251 (below pathogenic threshold
  • consistent with benign).
  • BayesDel score -0.25851 (negative
  • predicting benign).
  • SpliceAI max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 A different pathogenic missense change at the same amino acid residue (Pro108) has not been reported in ClinVar or the literature. There are no comparator variants at this position to satisfy PS1. Details ▾Hide ▴
Evidence considered
  • No pathogenic or likely pathogenic variant at residue Pro108 was identified in ClinVar.
Sources
clinvar ↗
PS2 No de novo occurrence with confirmed paternity and maternity has been reported for this variant in the literature or available case data. Details ▾Hide ▴
Evidence considered
  • No de novo data available for this variant.
Still missing
  • No parental or trio sequencing data available.
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_000075.3:c.322C>T (p.Pro108Ser) or a systematically characterized range that includes this position. Computational predictions alone (REVEL 0.251, BayesDel -0.25851) do not constitute functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB reports unknown oncogenic effect with no variant-specific functional data. No functional studies identified in literature.
Still missing
  • No experimental functional characterization of this variant exists.
Sources
oncokb ↗revelbayesdel
PS4 No case-control studies or cohort analyses demonstrate enrichment of this variant in affected individuals compared to controls. The variant has not been reported in any clinical case series. Details ▾Hide ▴
Evidence considered
  • No case-control or cohort data available for this variant.
Still missing
  • No prevalence data in affected populations versus controls.
PM1 This variant (p.Pro108Ser) does not lie within a statistically significant mutational hotspot as assessed by cancerhotspots.org, and no literature was identified characterizing residue Pro108 as part of a critical functional domain with established pathogenic missense variation. Residue PM1 requires a mutational hotspot or a well-characterized functional domain where missense variants are established as pathogenic. Details ▾Hide ▴
Evidence considered
  • No cancerhotspots.org significance at this residue. No domain-level functional studies identified for CDK4 residue 108.
Still missing
  • No critical domain characterization specific to CDK4 Pro108 was identified.
PM5 No different pathogenic missense variant has been reported at the same amino acid residue (Pro108) in CDK4. Automated PM5 candidate harvesting found zero same-residue comparator variants in ClinVar, and manual review confirmed no candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue pathogenic or likely pathogenic comparator variants identified at CDK4 Pro108.
Sources
clinvar ↗
PM6 No de novo observation (without confirmation of paternity) has been reported for this variant in the literature or available case data. Details ▾Hide ▴
Evidence considered
  • No de novo data available for this variant.
Still missing
  • No parental or trio sequencing data available.
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family studies or pedigree data available.
PP2 PP2 requires a gene with a low rate of benign missense variation (typically Z-score > 3.09) where missense variants are a common disease mechanism. While CDK4 has known pathogenic activating missense variants in melanoma (e.g., R24C/H), constraint metrics establishing a low rate of benign missense variation were not available for this assessment. Details ▾Hide ▴
Evidence considered
  • Insufficient constraint data (no Z-score or missense constraint metrics available) to establish low rate of benign missense variation.
Still missing
  • gnomAD missense constraint metrics (Z-score
  • oe ratio) not available.
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.251 (below the 0.5 pathogenic threshold), BayesDel score is -0.25851 (negative, indicating benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All available computational tools suggest a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.251 (below pathogenic threshold of 0.5).
  • BayesDel score -0.25851 (negative
  • consistent with benign).
  • SpliceAI max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No phenotypic data or clinical history is available for the individual carrying this variant to assess phenotype specificity for a CDK4-associated disorder. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • No clinical phenotype or family history provided.
PP5 This variant is absent from ClinVar entirely; no reputable source has classified it as pathogenic. Under the applicable rules, a ClinVar entry with at least 3-star expert panel review would be required to apply PP5 at supporting strength, but no ClinVar entry exists for this variant. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar with zero submissions and no expert panel review.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the 1% threshold required for BA1 (stand-alone benign). Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% across all gnomAD populations
  • below the BA1 threshold of >1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the 0.3% threshold required for BS1 (strong benign). Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% across all gnomAD populations
  • below the BS1 threshold of >0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data are available regarding the observation of this variant in healthy adult controls with full penetrance expected at an early age. BS2 requires observation in a healthy adult individual for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
  • No control cohort data or healthy individual observations available.
Still missing
  • No population control data beyond gnomAD.
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. While in silico predictors are consistent with a benign effect (REVEL 0.251, BayesDel -0.25851, SpliceAI 0.01), computational predictions do not constitute the well-established functional evidence required for BS3. Details ▾Hide ▴
Evidence considered
  • Computational predictions suggest benign effect
  • but no experimental functional studies exist for this variant.
Still missing
  • No experimental functional characterization of this variant exists.
Sources
revelbayesdelspliceai ↗
BS4 No segregation data are available to demonstrate lack of co-segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family studies or pedigree data available.
BP1 BP1 applies when a missense variant is found in a gene for which primarily truncating variants cause disease. CDK4-associated familial melanoma is caused by gain-of-function missense variants (e.g., p.Arg24Cys/His), not primarily by truncating loss-of-function variants. Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • CDK4 disease mechanism is activating missense
  • not primarily truncating loss-of-function.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in a dominant disorder. Details ▾Hide ▴
Evidence considered
  • No phase data or co-occurrence data available.
Still missing
  • No variant phasing or co-occurrence data available.
BP5 No data are available demonstrating that this variant is found in a case with an alternate molecular basis for disease. BP5 requires identification of another pathogenic variant that explains the phenotype in the same individual. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • No clinical or molecular data from the proband available.
BP6 This variant is absent from ClinVar entirely; no reputable source has classified it as benign. Under the applicable rules, a ClinVar entry with at least 3-star expert panel review would be required to apply BP6, but no ClinVar entry exists for this variant. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar with zero submissions and no expert panel review.
Sources
clinvar ↗
PS5 This variant is absent from ClinVar entirely; no reputable source has classified it as pathogenic. PS5 requires at least a database entry with pathogenic classification from a reputable source. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar with zero submissions.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.322C>T, p.Pro108Ser) and does not fall into the null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798): nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense substitution (bucket=other) does not qualify for PVS1 under PMC6185798.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders where a pathogenic variant is observed in trans. CDK4 is associated with autosomal dominant familial melanoma; recessive inheritance is not established. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant (c.322C>T) is a missense substitution (p.Pro108Ser), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Identifiers

Gene
CDK4
Transcript
NM_000075.3
Coding (HGVS c.)
NM_000075.3:c.322C>T
Protein (HGVS p.)
NP_000066.1:p.(Pro108Ser)
GRCh38
chr12:57751239 G>A
GRCh37
chr12:58145022 G>A

Gene diagram

Every interpreted variant in CDK4, mapped onto the exon structure of NM_000075.3. Select a row to find it on the plot.

CDK4NM_000075.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -101 bp
0.010
SpliceAI acceptor gainat +32 bp
0.000
SpliceAI donor lossat -313 bp
0.000
SpliceAI donor gainat +261 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.251
BayesDel
-0.259

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.251 (below the 0.5 pathogenic threshold and within the indeterminate-to-benign range), BayesDel score is -0.25851 (negative, indicating a benign prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). Three independent computational predictors are concordant in suggesting a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.251 (below pathogenic threshold
  • consistent with benign).
  • BayesDel score -0.25851 (negative
  • predicting benign).
  • SpliceAI max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.251 (below the 0.5 pathogenic threshold), BayesDel score is -0.25851 (negative, indicating benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All available computational tools suggest a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.251 (below pathogenic threshold of 0.5).
  • BayesDel score -0.25851 (negative
  • consistent with benign).
  • SpliceAI max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant (c.322C>T) is a missense substitution (p.Pro108Ser), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.251. BayesDel score = -0.25851.

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 Captured gnomAD v4.1 source record 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

Absent from gnomAD v4.1.

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 = 0.251. BayesDel score = -0.25851.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.

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.