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CDK12c.3424T>AUncertain significance
Print report
Variant interpretation report

CDK12 c.3424T>A, p.(Ser1142Thr)

NM_016507.4:c.3424T>A NP_057591.2:p.(Ser1142Thr) 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
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the PM2 criterion for absence from large population databases (allele frequency < 0.1% in non-VCEP generic ACMG framework).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.142 (well below pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). This satisfies BP4 as multiple independent in silico predictors concur on 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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. 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
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 · 21 not met · 0 not assessed · 6 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_016507.4:c.3424T>A (p.Ser1142Thr) is a missense variant in CDK12 exon 13.

This variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at moderate strength.

Multiple lines of computational evidence predict a benign effect: REVEL score 0.142, BayesDel score -0.294, and SpliceAI max delta 0.00, satisfying BP4 at supporting benign strength.

The variant is absent from ClinVar and COSMIC; no functional data, segregation data, or case-control data are available.

PVS1 is not applicable as this is a missense variant, not a predicted null variant.

Overall, one moderate pathogenic criterion (PM2) is met, and one supporting benign criterion (BP4) is met. Per the ACMG/AMP 2015 combination rules, a single moderate criterion with a supporting benign criterion results in a classification of Variant of Uncertain Significance (VUS).

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the PM2 criterion for absence from large population databases (allele frequency < 0.1% in non-VCEP generic ACMG framework). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: REVEL score 0.142 (well below pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). This satisfies BP4 as multiple independent in silico predictors concur on a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.142 (benign-range)
  • BayesDel -0.294 (negative
  • benign)
  • SpliceAI max delta 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 No established pathogenic variant with the same amino acid change (p.Ser1142Thr) has been reported in ClinVar; this variant is absent from all ClinVar records. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no same-amino-acid pathogenic comparator identified
Sources
clinvar ↗
PS2 No de novo occurrence with confirmed parentage has been reported for this variant in any available source. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar
  • publications
  • or case materials
Still missing
  • No clinical or family data available for this case
PS3 No variant-specific functional data are available. REVEL score is 0.142 and BayesDel score is -0.294, both consistent with a benign in silico prediction. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
  • REVEL 0.142 (below pathogenic threshold)
  • BayesDel -0.294 (negative/benign)
  • OncoKB: Unknown Oncogenic Effect
Still missing
  • No experimental functional studies of this variant or a systematically characterized range that includes it
Sources
revelbayesdeloncokb ↗
PS4 No case-control or prevalence data are available comparing affected individuals to controls for this variant. Details ▾Hide ▴
Evidence considered
  • No case-control or cohort data specific to this variant identified
Still missing
  • No affected-vs-control prevalence data available
PM1 Residue Ser1142 lies in the C-terminal region of CDK12, well outside the characterized kinase domain (approx. residues 719-983). This position is not within a statistically significant mutational hotspot per cancerhotspots.org, and no variant-specific or residue-specific functional domain evidence is available in the case materials to support PM1. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant hotspot (cancerhotspots.org)
  • Residue 1142 is C-terminal to the kinase domain
  • No characterized functional domain at this position
PM5 No pathogenic missense variant at the same codon (Ser1142) has been identified in ClinVar. The automated PM5 candidate search returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue PM5 candidates identified
  • No ClinVar entries at codon 1142
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence (with or without confirmed parentage) has been reported for this variant in any available clinical or literature source. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in any source
Still missing
  • No clinical or family data available
PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No family or segregation data
PP2 Missense constraint metrics for CDK12 are not available (HCI prior not found); no evidence that CDK12 has a low rate of benign missense variation. PP2 cannot be applied without supporting constraint data. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for CDK12
  • No gnomAD missense Z-score data in evidence brief
Still missing
  • No missense constraint metrics available for CDK12
PP3 Multiple computational tools predict a benign effect: REVEL score 0.142 (well below the 0.5 pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These lines of evidence do not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.142 (benign-range)
  • BayesDel -0.294 (negative
  • benign prediction)
  • SpliceAI max delta 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history information is available for this case to evaluate phenotypic specificity. Details ▾Hide ▴
Evidence considered
  • No phenotype data available
Still missing
  • No clinical phenotype or family history provided
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic. PP5 cannot be applied without a ClinVar entry classified as pathogenic/likely pathogenic by a qualified submitter. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no P/LP classification from any submitter
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency > 5% in any general population, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all available population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from all population databases. BS1 requires an allele frequency greater than expected for the disorder (> 0.3% in non-VCEP generic ACMG framework), which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all available population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 This variant has not been observed in any healthy adult individuals in gnomAD. BS2 requires observation in healthy adults for a fully penetrant disorder, which cannot be satisfied by absence. Details ▾Hide ▴
Evidence considered
  • No observations in healthy adults available
BS3 No well-established functional studies demonstrate a benign effect for this variant. Computational predictions (REVEL 0.142, BayesDel -0.294) are suggestive but do not constitute the well-established functional evidence required for BS3. Details ▾Hide ▴
Evidence considered
  • No variant-specific experimental functional data available
Still missing
  • No experimental functional characterization of this variant
BS4 No segregation data are available to evaluate non-segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation or family data available
Still missing
  • No family or segregation data
BP1 CDK12 is not established as a gene where only truncating variants cause disease. Germline CDK12 variants of multiple types (including missense) are reported in association with prostate cancer, and the mechanism is not exclusively loss-of-function by truncation. Details ▾Hide ▴
Evidence considered
  • CDK12 germline disease association is not limited to truncating variants
Sources
pvs1_gene_context
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • No trans-configuration data available
Still missing
  • No data on allelic configuration with other variants
BP5 This variant is absent from ClinVar; no reputable source has reported it as benign. BP5 cannot be applied without evidence that an alternate molecular basis explains disease in a case harboring this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified in available data
Still missing
  • No clinical case data available
BP6 This variant is absent from ClinVar; no reputable source has reported it as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no B/LB classification from any submitter
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_016507.4:c.3424T>A is a missense variant (p.Ser1142Thr) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution at c.3424
  • variant bucket 'other' per PVS1 variant assessment
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders. CDK12-associated disease is not recessively inherited. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length-changing variants (indels, stop-loss). This is a single-nucleotide missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions. This is a single-nucleotide substitution, not an indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_016507.4:c.3424T>A is a missense variant (p.Ser1142Thr), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous
PS5 N/APS5 is not defined in the ACMG/AMP 2015 framework employed for this case. No alternate framework or evidence source provides an applicable PS5 rule. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CDK12
Transcript
NM_016507.4
Coding (HGVS c.)
NM_016507.4:c.3424T>A
Protein (HGVS p.)
NP_057591.2:p.(Ser1142Thr)
GRCh38
chr17:39525980 T>A
GRCh37
chr17:37682233 T>A

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 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 +10 bp
0.000
SpliceAI acceptor gainat +78 bp
0.000
SpliceAI donor lossat +336 bp
0.000
SpliceAI donor gainat +371 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.142
BayesDel
-0.294

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: REVEL score 0.142 (well below pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). This satisfies BP4 as multiple independent in silico predictors concur on a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.142 (benign-range)
  • BayesDel -0.294 (negative
  • benign)
  • SpliceAI max delta 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
PP3 Multiple computational tools predict a benign effect: REVEL score 0.142 (well below the 0.5 pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These lines of evidence do not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.142 (benign-range)
  • BayesDel -0.294 (negative
  • benign prediction)
  • SpliceAI max delta 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_016507.4:c.3424T>A is a missense variant (p.Ser1142Thr), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.142. BayesDel score = -0.294312.

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 0.000 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

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 = 0.00). REVEL score = 0.142. BayesDel score = -0.294312.

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.