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CDK12c.1601C>TUncertain significance
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Variant interpretation report

CDK12 c.1601C>T, p.(Ser534Phe)

NM_016507.4:c.1601C>T NP_057591.2:p.(Ser534Phe) 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 CDK12

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
PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF=6.20e-7; 1/1,613,138 alleles; 0 homozygotes), well below the 0.1% threshold for PM2.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence consistently predict no impact on gene product: REVEL score 0.104 (benign range), BayesDel score -0.262 (benign range), and SpliceAI max delta 0.01 (no predicted splice effect). Three independent in silico tools uniformly suggest 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 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.

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
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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. CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV71000764, n = 1 times).

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.

26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2 (supporting) is met: the variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-7, 1/1,613,138 alleles), well below the 0.1% threshold.

BP4 (supporting benign) is met: multiple lines of computational evidence (REVEL 0.104, BayesDel -0.262, SpliceAI max delta 0.01) consistently predict no impact on gene product.

The total evidence weight is one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). Under generic ACMG/AMP 2015 combination rules, this does not meet the threshold for Likely Pathogenic (requires ≥2 supporting), Likely Benign (requires ≥2 supporting benign), or any other classification tier. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingThe variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF=6.20e-7; 1/1,613,138 alleles; 0 homozygotes), well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: 1 allele out of 1
  • 613
  • 138 (AF=6.20e-7).
  • gnomAD-Canada v1.0: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence consistently predict no impact on gene product: REVEL score 0.104 (benign range), BayesDel score -0.262 (benign range), and SpliceAI max delta 0.01 (no predicted splice effect). Three independent in silico tools uniformly suggest a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.104 (benign
  • below 0.29 threshold).
  • BayesDel: -0.262 (benign range).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No evidence that the same amino acid change (p.Ser534Phe) has been previously established as pathogenic in ClinVar, literature, or other curated databases. Details ▾Hide ▴
Evidence considered
  • ClinVar single submitter classifies as VUS
  • not pathogenic.
  • OncoKB: Unknown Oncogenic Effect.
Still missing
  • No prior pathogenic assertion for p.Ser534Phe.
Sources
clinvar ↗oncokb ↗
PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PS3 No well-established functional studies demonstrating a damaging effect have been identified for this variant. OncoKB classifies the variant as Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with experimental characterization of p.Ser534Phe were found. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
  • No publications identified with functional data for this variant.
Still missing
  • No functional studies available for p.Ser534Phe.
Sources
oncokb ↗
PS4 No case-control or cohort prevalence data comparing the frequency of this variant in affected individuals versus controls is available. Details ▾Hide ▴
Still missing
  • No case-control or enrichment data.
PM1 The variant (p.Ser534Phe) is not located in a statistically significant mutational hotspot per CancerHotspots.org. Residue S534 lies in the serine/arginine-rich N-terminal region of CDK12, not within the C-terminal kinase domain. No well-characterized critical functional domain has been established encompassing this residue. Details ▾Hide ▴
Evidence considered
  • CancerHotspots.org: residue not significant.
  • S534 is in the SR-rich region
  • not the kinase domain.
Still missing
  • No domain-level hotspot data for S534.
Sources
oncokb ↗
PM5 No same-residue pathogenic comparator variant was identified. Automated PM5 candidate harvesting found no eligible candidates for residue S534 of CDK12. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: no eligible same-residue comparators found.
Still missing
  • No same-residue pathogenic variant in ClinVar for comparison.
Sources
pm5_candidates
PM6 No assumed de novo observation (without confirmation of paternity and maternity) has been reported for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No cosegregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data.
PP2 No HCI prior score is available for CDK12. Cannot assess whether the gene has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported for CDK12.
Still missing
  • No HCI prior data for CDK12.
PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.104 (benign range, below 0.29 threshold) and BayesDel score -0.262 (benign range). These do not support a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.104 (benign-predicting).
  • BayesDel: -0.262 (benign-predicting).
Sources
revelbayesdel
PP4 No patient phenotype or family history data are available for this case to assess specificity for CDK12-associated disease. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
PP5 ClinVar classification is Uncertain Significance (1-star, criteria provided, single submitter, Ambry Genetics). PP5 requires a reputable source to report the variant as pathogenic, which is not met. The ClinVar submission is not from an expert panel and does not reach the 3-star threshold. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • 1-star
  • single submitter (Ambry Genetics).
Sources
clinvar ↗
BA1 The variant allele frequency in gnomAD v4.1 is 6.20e-7 (0.000062%), far below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=6.20e-7
  • well below 1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant allele frequency in gnomAD v4.1 is 6.20e-7, far below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=6.20e-7
  • well below 0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available on observation of this variant in healthy adults to assess whether it occurs in the absence of disease. Details ▾Hide ▴
Still missing
  • No healthy adult observation data.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this variant. In silico predictors alone do not constitute well-established functional evidence for BS3. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional studies identified.
Still missing
  • No functional studies demonstrating benign effect.
BS4 No segregation data are available to assess lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP1 Although CDK12 loss-of-function is a supported disease mechanism in germline prostate cancer, missense variants in CDK12 can also be pathogenic (particularly within the kinase domain). BP1 is reserved for genes in which only truncating variants cause disease, which is not established for CDK12. Details ▾Hide ▴
Evidence considered
  • CDK12 LOF mechanism is supported
  • but missense variants are not excluded as a disease mechanism.
Sources
pvs1_gene_context
BP2 No data on observation of this variant in trans with a known pathogenic variant in CDK12 are available. Details ▾Hide ▴
Still missing
  • No trans-phase data.
BP5 No data are available on a case harboring this variant with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data.
BP6 ClinVar classification is Uncertain Significance (1-star), not benign. BP6 requires a reputable source to report the variant as benign, which is not met. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • 1-star
  • single submitter — not a benign assertion.
Sources
clinvar ↗
PS5 No data available to support this criterion; no evidence of multiple unrelated probands with the same phenotype or other strong pathogenic assertions. Details ▾Hide ▴
Still missing
  • No proband or phenotype data available.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_016507.4:c.1601C>T is a missense variant (p.Ser534Phe). It does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 534
  • PVS1 null-variant criteria not met.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ANM_016507.4:c.1601C>T is a missense variant (p.Ser534Phe), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Identifiers

Gene
CDK12
Transcript
NM_016507.4
Coding (HGVS c.)
NM_016507.4:c.1601C>T
Protein (HGVS p.)
NP_057591.2:p.(Ser534Phe)
GRCh38
chr17:39471433 C>T
GRCh37
chr17:37627686 C>T
ClinVar
3830749
COSMIC
COSV71000764

Gene diagram

Every interpreted variant in CDK12, mapped onto the exon structure of NM_016507.4. Select a row to find it on the plot.

CDK12NM_016507.4
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,138 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 / 1,613,138 alleles · 0 hom
East Asian1 / 44,872 2.2e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, 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= 6.1991e-07; MAF= 0.00006%, 1/1613138 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22856e-05; MAF= 0.00223%, 1/44872 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 -171 bp
0.000
SpliceAI acceptor gainat +194 bp
0.010
SpliceAI donor lossat +330 bp
0.000
SpliceAI donor gainat -188 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.020

Other predictors

REVEL
0.104
BayesDel
-0.262

How the predictions were used

BP4 SupportingMultiple lines of computational evidence consistently predict no impact on gene product: REVEL score 0.104 (benign range), BayesDel score -0.262 (benign range), and SpliceAI max delta 0.01 (no predicted splice effect). Three independent in silico tools uniformly suggest a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.104 (benign
  • below 0.29 threshold).
  • BayesDel: -0.262 (benign range).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.104 (benign range, below 0.29 threshold) and BayesDel score -0.262 (benign range). These do not support a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.104 (benign-predicting).
  • BayesDel: -0.262 (benign-predicting).
Sources
revelbayesdel
BP7 N/ANM_016507.4:c.1601C>T is a missense variant (p.Ser534Phe), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.104. BayesDel score = -0.261965.

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 / 1,613,138 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 1 Uncertain significance 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= 6.1991e-07; MAF= 0.00006%, 1/1613138 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22856e-05; MAF= 0.00223%, 1/44872 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3830749)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.104. BayesDel score = -0.261965.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV71000764, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.