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CDK2c.665C>TUncertain significance
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Variant interpretation report

CDK2 c.665C>T, p.(Pro222Leu)

NM_001798.4:c.665C>T NP_001789.2:p.(Pro222Leu) 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 CDK2

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 absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 population databases, consistent with a rare variant.

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
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. 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 ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

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 · 5 not met · 18 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_001798.4:c.665C>T (p.Pro222Leu) in CDK2 is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2 at supporting strength.

No other ACMG/AMP criterion was met. The variant lacks ClinVar classification, functional studies, de novo observations, segregation data, hotspot localization, same-residue pathogenic comparators, and conclusive in silico evidence.

With only one supporting criterion (PM2_supporting) and no other criteria met in either the pathogenic or benign direction, this variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules (PMID:25741868).

Met · 1

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • absent from gnomAD v4.1 (0 alleles)
  • absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 5 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant mutational hotspot (CancerHotspots). Residue 222 resides within the CDK2 kinase domain, but no evidence was provided that this is a well-established critical functional domain lacking benign missense variation in the germline disease context. Details ▾Hide ▴
Evidence considered
  • CancerHotspots reports no significant hotspot at this residue. No domain-specific constraint data available for CDK2 germline disease.
Still missing
  • No CDK2 germline disease-specific domain criticality data (e.g.
  • ClinGen domain track).
PP3 In silico evidence is equivocal. REVEL score is 0.661 (below the 0.75 threshold typically used for computational pathogenicity support), BayesDel score is -0.044 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.02). These do not constitute multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.661
  • BayesDel -0.044
  • SpliceAI max delta 0.02.
Sources
revelbayesdelspliceai ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1 population databases. Allele frequency is 0%, far below the BA1 threshold of >5%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 0%
  • gnomAD v4.1 AF: 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from population databases (gnomAD v2.1, v4.1). Allele frequency does not exceed the expected prevalence threshold for a rare disorder. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 0%
  • gnomAD v4.1 AF: 0%
  • does not exceed BS1 >0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 In silico evidence is equivocal and does not constitute multiple lines of computational evidence suggesting no impact. REVEL 0.661 is above the benign range; BayesDel -0.044 is mildly benign-leaning; SpliceAI max delta 0.02 shows no splicing effect. The aggregate evidence is insufficient for BP4. Details ▾Hide ▴
Evidence considered
  • REVEL 0.661 (not in benign range)
  • BayesDel -0.044
  • SpliceAI max delta 0.02.
Sources
revelbayesdelspliceai ↗

Not assessed · 18 · no assessment recorded

PS1 No known pathogenic nucleotide change at the same position (c.665) producing the same amino acid change (p.Pro222Leu) was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for this variant or any same-amino-acid-change comparator at c.665.
Still missing
  • No variant-specific publications to review for alternative nucleotide changes at c.665.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation of NM_001798.4:c.665C>T was identified in the literature or ClinVar. No parentage-confirmed de novo reports are available. Details ▾Hide ▴
Still missing
  • No de novo reports available for this variant.
Sources
clinvar ↗
PS3 No well-established in vitro or in vivo functional studies were identified for this specific variant (NM_001798.4:c.665C>T, p.Pro222Leu) in CDK2. Details ▾Hide ▴
Still missing
  • No functional study data available for this variant.
PS4 No case-control data or statistical enrichment analysis was identified for this variant in any disease cohort. Details ▾Hide ▴
Still missing
  • No case-control or prevalence data available for this variant.
PM5 No same-residue pathogenic comparator variants (different missense change at Pro222) were identified in ClinVar. PM5 candidate harvesting yielded zero comparators; no published alternative missense at residue 222 was found. Details ▾Hide ▴
Evidence considered
  • Zero same-residue comparators available to support PM5.
Still missing
  • No pathogenic comparator variants at Pro222 available.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation of NM_001798.4:c.665C>T was identified. PM6 requires a de novo observation (with or without confirmed parentage), and none was found in ClinVar or the literature. Details ▾Hide ▴
Still missing
  • No de novo reports available for this variant.
Sources
clinvar ↗
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family-based segregation data available.
PP2 HCI prior scores are not available for CDK2. Without missense constraint metrics (e.g., Z-score, missense depletion), it cannot be determined whether CDK2 has a low rate of benign missense variation to support PP2. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for CDK2
  • no constraint data available.
Still missing
  • No missense constraint data (Z-score
  • gnomAD missense o/e) available for CDK2.
PP4 No patient phenotype information is available. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
PP5 No reputable source (e.g., ClinGen-recognized expert panel, clinical diagnostic laboratory) has reported this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no expert classification available.
Still missing
  • No expert or clinical laboratory classification available.
Sources
clinvar ↗
BS2 No observation of this variant in a healthy adult individual has been reported for a fully penetrant disorder. No genotype-phenotype data available. Details ▾Hide ▴
Still missing
  • No observation data in healthy individuals.
BS3 No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for NM_001798.4:c.665C>T in CDK2. Details ▾Hide ▴
Still missing
  • No functional studies available evaluating the effect of p.Pro222Leu.
BS4 No nonsegregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family-based nonsegregation data available.
BP1 While loss of function is supported as a CDK2 germline disease mechanism (pvs1_gene_context: lof_mechanism_supported=true), CDK2 is not an established disease gene where primarily truncating variants are known to cause disease. Insufficient evidence to apply BP1. Details ▾Hide ▴
Evidence considered
  • CDK2 LoF mechanism supported but gene lacks established clinical validity for BP1 application.
Still missing
  • CDK2 is not a ClinGen-curated gene-disease pair with established truncating-variant disease mechanism.
BP2 No observation of this variant in trans with a known pathogenic variant in CDK2 was identified. Details ▾Hide ▴
Still missing
  • No trans-configuration data available.
BP5 No observation of this variant in a case where an alternate molecular basis for disease was identified. Details ▾Hide ▴
Still missing
  • No alternate-molecular-basis observation data available.
BP6 No reputable source reports this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no benign classification available.
Still missing
  • No expert or clinical laboratory benign classification available.
Sources
clinvar ↗
PS5 No alternative pathogenic missense change at residue Pro222 was identified. The PM5 candidate search returned zero same-residue comparators; ClinVar contains no entries for this variant. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvesting yielded no same-residue pathogenic comparators at Pro222.
Still missing
  • No pathogenic comparator variants at residue 222 available.
Sources
pm5_candidatesclinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.665C>T, p.Pro222Leu) that does not fall into the PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
  • Missense substitution Pro222Leu is outside the scope of generic PVS1 null-variant criteria.
Sources
pvs1_generic_framework ↗
PM3 N/ANo second pathogenic variant in trans was identified. PM3 is for recessive disorders; no recessive CDK2 disorder is established, and no trans observation data exist. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis variant is a single-nucleotide missense substitution (c.665C>T), not a protein-length-altering in-frame deletion or insertion or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis variant is a single-nucleotide missense substitution, not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.665C>T, p.Pro222Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Identifiers

Gene
CDK2
Transcript
NM_001798.4
Coding (HGVS c.)
NM_001798.4:c.665C>T
Protein (HGVS p.)
NP_001789.2:p.(Pro222Leu)
GRCh38
chr12:55971120 C>T
GRCh37
chr12:56364904 C>T

Gene diagram

Every interpreted variant in CDK2, mapped onto the exon structure of NM_001798.4. Select a row to find it on the plot.

CDK2NM_001798.4
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 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -48 bp
0.000
SpliceAI acceptor gainat +401 bp
0.020
SpliceAI donor lossat -379 bp
0.000
SpliceAI donor gainat +127 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.661
BayesDel
-0.044

How the predictions were used

PP3 In silico evidence is equivocal. REVEL score is 0.661 (below the 0.75 threshold typically used for computational pathogenicity support), BayesDel score is -0.044 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.02). These do not constitute multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.661
  • BayesDel -0.044
  • SpliceAI max delta 0.02.
Sources
revelbayesdelspliceai ↗
BP4 In silico evidence is equivocal and does not constitute multiple lines of computational evidence suggesting no impact. REVEL 0.661 is above the benign range; BayesDel -0.044 is mildly benign-leaning; SpliceAI max delta 0.02 shows no splicing effect. The aggregate evidence is insufficient for BP4. Details ▾Hide ▴
Evidence considered
  • REVEL 0.661 (not in benign range)
  • BayesDel -0.044
  • SpliceAI max delta 0.02.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.665C>T, p.Pro222Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.661. BayesDel score = -0.0440517.

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 0.020 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 ↗

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.

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 = 0.661. BayesDel score = -0.0440517.

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.