NM_016507.4:c.86G>C

CDK12 · NP_057591.2:p.(Ser29Thr) · NM_016507.4

GRCh37: chr17:37618410 G>C · GRCh38: chr17:39462157 G>C

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.(Ser29Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_016507.4:c.86G>C (p.Ser29Thr) is a missense variant in CDK12 absent from population databases (gnomAD v2.1 and v4.1), supporting PM2 at supporting strength.

Multiple in silico predictors (REVEL 0.176, BayesDel -0.320, SpliceAI 0.00) support a benign effect, meeting BP4 at supporting strength.

No functional studies, case-control data, segregation data, de novo reports, ClinVar classifications, or same-residue pathogenic comparators were identified for this variant.

The variant does not fall within a known functional domain or mutational hotspot, and PVS1 is not applicable as this is a missense substitution.

Overall, PM2 (supporting) and BP4 (supporting) are the only criteria met, yielding a classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules — PM2 and BP4 with equal supporting-level evidence in opposing directions do not reach pathogenic or likely benign thresholds.

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.86G>C is a missense variant (p.Ser29Thr) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant at the same amino acid position (p.Ser29) has been identified in ClinVar or the literature.	clinvar
PS2	Not met	No de novo data are available for this variant; no reports of confirmed parentage with this variant absent from both parents were identified.
PS3	Not met	No functional studies were identified for this variant or for a systematically characterized range that includes p.Ser29. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control studies or cohort data demonstrating enrichment of this variant in affected individuals versus controls were identified.
PS5	Not met	No previously established pathogenic variant at the same amino acid position (p.Ser29) regardless of nucleotide change has been identified.	clinvar
PM1	Not met	Residue p.Ser29 lies in the N-terminal region of CDK12, far upstream of the kinase domain (residues ~720–980), and is not within a well-characterized critical functional domain. This position is not a statistically significant mutational hotspot (cancerhotspots.org).	oncokb
PM2	Met	NM_016507.4:c.86G>C is absent from gnomAD v2.1 and v4.1, consistent with a population frequency below 0.1% (PM2).	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic variant at the same amino acid residue (p.Ser29) with a different missense change was identified in ClinVar or the literature.	pm5_candidates clinvar
PM6	Not met	No de novo event has been reported for this variant with confirmed parentage.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	Not met	Insufficient data to confirm that CDK12 has a low rate of benign missense variation and that missense variants are a common mechanism of disease. HCI prior score is not available for this gene.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold), BayesDel score -0.320 (negative), and SpliceAI max delta 0.00 (no predicted splicing impact).	revel bayesdel spliceai
PP4	Not met	No specific phenotype or clinical data are available for the individual carrying this variant.
PP5	Not met	This variant is absent from ClinVar; no pathogenic classification from a reputable source is available.	clinvar
BA1	Not met	NM_016507.4:c.86G>C is absent from population databases; the allele frequency does not exceed the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from population databases; the allele frequency does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on healthy adult homozygotes or hemizygotes for this variant.
BS3	Not met	No functional studies demonstrating no deleterious effect have been identified for this variant.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease in affected families.
BP1	Not met	CDK12 germline disease mechanism is not exclusively mediated by truncating variants; both missense and truncating variants have been reported in association with prostate cancer. Insufficient evidence to apply BP1.
BP2	Not met	No data on co-occurrence of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide missense substitution.
BP4	Met	Multiple lines of in silico evidence predict a benign effect: REVEL score 0.176 (below pathogenic threshold), BayesDel score -0.320 (negative, benign range), and SpliceAI max delta 0.00 (no predicted splicing impact).	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in the case to suggest this variant is not causative.
BP6	Not met	This variant is absent from ClinVar; no benign classification from a reputable source is available.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact; NM_016507.4:c.86G>C is a missense variant (p.Ser29Thr).
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant; CDK12-associated disease is not established as recessive.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions in non-repeat regions; this is a single-nucleotide missense substitution.

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