NM_016507.4:c.4099G>A (p.Val1367Ile) in CDK12 meets PM2 at supporting level: absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (1/1,614,182 alleles, AF=6.2×10⁻⁷).1 BP4 is met at supporting level: multiple computational tools consistently predict a benign effect, including REVEL 0.092, BayesDel −0.587, and SpliceAI max delta 0.02.2 PVS1 is not applicable (missense substitution). All other assessed criteria (PS1–PS5, PM1, PM5–PM6, PP1–PP5, BA1, BS1–BS4, BP1–BP2, BP5–BP7) are not met due to absence of variant-specific clinical, functional, segregation, or de novo evidence.3 One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. Under generic ACMG/AMP 2015 combination rules, this yields conflicting evidence — insufficient to classify as pathogenic, likely pathogenic, likely benign, or benign. The overall classification is Variant of Uncertain Significance (VUS).4
CDK12
Final classification
VUS
PM2BP4
CDK12
c.4099G>A
p.Val1367Ile
This variant
NM_016507.4:c.4099G>A (p.Val1367Ile) in CDK12 meets PM2 at supporting level: absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (1/1,614,182 alleles, AF=6.2×10⁻⁷).
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDK12 c.4099G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
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 · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at extremely low frequency in gnomAD v4.1 (1/1,614,182 alleles, AF=6.2×10⁻⁷, highest subpopulation AF=1.33×10⁻⁵ in African/African American). The total allele frequency is well below the 0.1% PM2 threshold. No homozygotes observed.
Absent from gnomAD v2.1Absent from gnomAD-Canada v1.0gnomAD v4.1: 1/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence consistently predict no damaging effect: REVEL score 0.092 (tolerated, well below the ~0.5 threshold for pathogenicity), BayesDel score −0.587 (benign range), and SpliceAI max delta score 0.02 (no predicted splicing impact). Three independent in silico tools concur on a benign interpretation.
REVEL: 0.092 (tolerated/benign — well below ~0.5 pathogenic threshold)BayesDel: -0.587 (benign)SpliceAI max delta: 0.02 (no predicted splice alteration)
Assessed · not applied
· 20 not met · 0 not assessed
Pathogenic
PS1
No alternative nucleotide change at c.4099 resulting in p.Val1367Ile has been established as pathogenic.
PS2
No de novo observation reported for this variant in any source, and no paternity/maternity confirmation data are available.
PS3
No well-established in vitro or in vivo functional studies demonstrate a damaging effect for NM_016507.4:c.4099G>A (p.Val1367Ile).
PS4
No case-control data demonstrate significantly increased prevalence of this variant in affected individuals versus controls.
PM1
Residue Val1367 is located in the C-terminal domain of CDK12 (amino acid 1367 of 1490), well outside the kinase domain (approximately residues 700–1050).
PM6
No de novo observation with unconfirmed parentage has been reported for this variant.
PP1
No cosegregation data with disease in multiple affected family members are available for this variant.
PP2
CDK12 disease mechanism involves loss-of-function variants (truncating, splice), not predominantly missense variation.
PP3
Multiple in silico tools consistently predict a benign or tolerated effect: REVEL score 0.092 (well below the ~0.5 pathogenic threshold), BayesDel score −0.587 (benign range), and SpliceAI max delta 0.02 (no predicted splice impact).
PP4
No clinical phenotype data are available for the individual(s) carrying this variant.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The allele frequency is 6.2×10⁻⁷ (0.00006%), far below the 1% BA1 threshold.
BS1
The allele frequency is 6.2×10⁻⁷ (0.00006%), well below the 0.3% BS1 threshold.
BS2
No observation in a healthy adult individual has been documented for a fully penetrant disorder context; clinical data for the single gnomAD carrier are unavailable.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease in affected family members.
BP1
While CDK12 loss-of-function variants are associated with disease, there is insufficient evidence that truncating variants are the sole or overwhelmingly predominant disease mechanism such that any missense variant can be considered likely benign under BP1.
BP2
No observation of this variant in trans with a pathogenic CDK12 variant (for a dominant disorder) or in cis with a pathogenic variant has been reported.
BP5
No alternate molecular basis for disease has been identified in an individual carrying this variant.
BP6
No reputable source has classified this variant as benign.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19509e-07; MAF= 0.00006%, 1/1614182 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33266e-05; MAF= 0.00133%, 1/75038 alleles, homozygotes = 0).
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
6.2e-05%
· 1 / 1,614,182
0 hom
0 hom
African/African American 1 / 75,038 |
0.0013% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3999469)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.092. BayesDel score = -0.587193.
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 previously been reported in somatic cancers (COSMIC; COSV71001028, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links