NM_016507.4:c.4099G>A

CDK12 · NP_057591.2:p.(Val1367Ile) · NM_016507.4

GRCh37: chr17:37687195 G>A · GRCh38: chr17:39530942 G>A

Gene: CDK12 Transcript: NM_016507.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CDK12

Transcript

NM_016507.4

Protein

NP_057591.2:p.(Val1367Ile)

gnomAD AF

6.195088286203166e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_016507.4:c.4099G>A is a missense substitution (p.Val1367Ile), not a null variant (nonsense, frameshift, or canonical splice ±1,2). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change at c.4099 resulting in p.Val1367Ile has been established as pathogenic. No same-amino-acid comparator data available.
PS2	Not met	No de novo observation reported for this variant in any source, and no paternity/maternity confirmation data are available.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a damaging effect for NM_016507.4:c.4099G>A (p.Val1367Ile). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. No variant-specific functional studies were identified in the literature.	oncokb
PS4	Not met	No case-control data demonstrate significantly increased prevalence of this variant in affected individuals versus controls. Observed once in COSMIC (somatic cancer, COSV71001028), but somatic occurrence does not satisfy germline PS4.	gnomad_v4 gnomad_v2
PS5	Not met	While CDK12 has been associated with prostate cancer in the germline context, no specific evidence links this variant to a well-established disease phenotype meeting the PS5 standard of a reputable source reporting it as pathogenic.	clinvar
PM1	Not met	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). Hotspot analysis does not identify this residue as a statistically significant mutational hotspot. No functional domain critical to disease pathogenesis has been established at this position.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic variant at the same residue (Val1367) was identified to support PM5 comparator analysis. The automated PM5 candidate harvest returned zero candidates.	pm5_candidates
PM6	Not met	No de novo observation with unconfirmed parentage has been reported for this variant.
PP1	Not met	No cosegregation data with disease in multiple affected family members are available for this variant.
PP2	Not met	CDK12 disease mechanism involves loss-of-function variants (truncating, splice), not predominantly missense variation. There is insufficient evidence that CDK12 has a low rate of benign missense variation and that missense variants are a common mechanism of disease, as required for PP2.	pvs1_gene_context
PP3	Not met	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). This evidence supports BP4 rather than PP3.	revel bayesdel spliceai
PP4	Not met	No clinical phenotype data are available for the individual(s) carrying this variant. The variant cannot be assessed for phenotype specificity to CDK12-associated disease.
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance (1 submitter, criteria provided, single submitter).	clinvar
BA1	Not met	The allele frequency is 6.2×10⁻⁷ (0.00006%), far below the 1% BA1 threshold. This variant is not common in any population.	gnomad_v4 gnomad_v2
BS1	Not met	The allele frequency is 6.2×10⁻⁷ (0.00006%), well below the 0.3% BS1 threshold. This variant is not observed at a frequency greater than expected for the disorder.	gnomad_v4 gnomad_v2
BS2	Not met	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	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. Although in silico predictors suggest a benign effect, computational evidence alone is insufficient to meet BS3.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease in affected family members.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in an individual carrying this variant.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar reports a single submission of Uncertain significance.	clinvar
BP7	N/A	NM_016507.4:c.4099G>A is a missense variant (p.Val1367Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing algorithms predict no impact.

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