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.1 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.2 The variant is absent from ClinVar and COSMIC; no functional data, segregation data, or case-control data are available.3 PVS1 is not applicable as this is a missense variant, not a predicted null variant.4 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).5
CDK12
Final classification
VUS
CDK12 c.3424T>A · p.Ser1142Thr
CDK12
NM_016507.4:c.3424T>A (p.Ser1142Thr) is a missense variant in CDK12 exon 13.
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.
Classification rationale
PM2
BP4
VUS
CDK12 c.3424T>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_016507.4 · variants mapped to exon structure
CDK12
NM_016507.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
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).
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
✓
BP4
supporting
Benign
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.
REVEL 0.142 (benign-range)BayesDel -0.294 (negativebenign)
Assessed · not applied
Pathogenic
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.
PS2
No de novo occurrence with confirmed parentage has been reported for this variant in any available source.
PS3
No variant-specific functional data are available.
PS4
No case-control or prevalence data are available comparing affected individuals to controls for this variant.
PM1
Residue Ser1142 lies in the C-terminal region of CDK12, well outside the characterized kinase domain (approx.
PM5
No pathogenic missense variant at the same codon (Ser1142) has been identified in ClinVar.
PM6
No de novo occurrence (with or without confirmed parentage) has been reported for this variant in any available clinical or literature source.
PP1
No segregation data are available for this variant in affected families.
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.
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).
PP4
No patient phenotype or family history information is available for this case to evaluate phenotypic specificity.
PP5
This variant is absent from ClinVar; no reputable source has reported it as pathogenic.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from all population databases.
BS2
This variant has not been observed in any healthy adult individuals in gnomAD.
BS3
No well-established functional studies demonstrate a benign effect for this variant.
BS4
No segregation data are available to evaluate non-segregation with disease.
BP1
CDK12 is not established as a gene where only truncating variants cause disease.
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP5
This variant is absent from ClinVar; no reputable source has reported it as benign.
BP6
This variant is absent from ClinVar; no reputable source has reported it as benign or likely benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links