NM_016507.4:c.1601C>T

CDK12 · NP_057591.2:p.(Ser534Phe) · NM_016507.4

GRCh37: chr17:37627686 C>T · GRCh38: chr17:39471433 C>T

Gene: CDK12 Transcript: NM_016507.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CDK12

Transcript

NM_016507.4

Protein

NP_057591.2:p.(Ser534Phe)

gnomAD AF

6.199097659344706e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting) is met: the variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-7, 1/1,613,138 alleles), well below the 0.1% threshold.

BP4 (supporting benign) is met: multiple lines of computational evidence (REVEL 0.104, BayesDel -0.262, SpliceAI max delta 0.01) consistently predict no impact on gene product.

The total evidence weight is one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). Under generic ACMG/AMP 2015 combination rules, this does not meet the threshold for Likely Pathogenic (requires ≥2 supporting), Likely Benign (requires ≥2 supporting benign), or any other classification tier. The variant is classified as a 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.1601C>T is a missense variant (p.Ser534Phe). It does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that the same amino acid change (p.Ser534Phe) has been previously established as pathogenic in ClinVar, literature, or other curated databases.	clinvar oncokb
PS2	Not met	No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3	Not met	No well-established functional studies demonstrating a damaging effect have been identified for this variant. OncoKB classifies the variant as Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with experimental characterization of p.Ser534Phe were found.	oncokb
PS4	Not met	No case-control or cohort prevalence data comparing the frequency of this variant in affected individuals versus controls is available.
PS5	Not met	No data available to support this criterion; no evidence of multiple unrelated probands with the same phenotype or other strong pathogenic assertions.
PM1	Not met	The variant (p.Ser534Phe) is not located in a statistically significant mutational hotspot per CancerHotspots.org. Residue S534 lies in the serine/arginine-rich N-terminal region of CDK12, not within the C-terminal kinase domain. No well-characterized critical functional domain has been established encompassing this residue.	oncokb
PM2	Met	The variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF=6.20e-7; 1/1,613,138 alleles; 0 homozygotes), well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue pathogenic comparator variant was identified. Automated PM5 candidate harvesting found no eligible candidates for residue S534 of CDK12.	pm5_candidates
PM6	Not met	No assumed de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1	Not met	No cosegregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	No HCI prior score is available for CDK12. Cannot assess whether the gene has a low rate of benign missense variation and whether missense variants are a common mechanism of disease.
PP3	Not met	Multiple lines of in silico evidence predict a benign effect: REVEL score 0.104 (benign range, below 0.29 threshold) and BayesDel score -0.262 (benign range). These do not support a damaging prediction.	revel bayesdel
PP4	Not met	No patient phenotype or family history data are available for this case to assess specificity for CDK12-associated disease.
PP5	Not met	ClinVar classification is Uncertain Significance (1-star, criteria provided, single submitter, Ambry Genetics). PP5 requires a reputable source to report the variant as pathogenic, which is not met. The ClinVar submission is not from an expert panel and does not reach the 3-star threshold.	clinvar
BA1	Not met	The variant allele frequency in gnomAD v4.1 is 6.20e-7 (0.000062%), far below the 1% threshold required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 6.20e-7, far below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on observation of this variant in healthy adults to assess whether it occurs in the absence of disease.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this variant. In silico predictors alone do not constitute well-established functional evidence for BS3.
BS4	Not met	No segregation data are available to assess lack of cosegregation with disease in affected family members.
BP1	Not met	Although CDK12 loss-of-function is a supported disease mechanism in germline prostate cancer, missense variants in CDK12 can also be pathogenic (particularly within the kinase domain). BP1 is reserved for genes in which only truncating variants cause disease, which is not established for CDK12.	pvs1_gene_context
BP2	Not met	No data on observation of this variant in trans with a known pathogenic variant in CDK12 are available.
BP4	Met	Multiple lines of computational evidence consistently predict no impact on gene product: REVEL score 0.104 (benign range), BayesDel score -0.262 (benign range), and SpliceAI max delta 0.01 (no predicted splice effect). Three independent in silico tools uniformly suggest a benign effect.	revel bayesdel spliceai
BP5	Not met	No data are available on a case harboring this variant with an alternate molecular basis for disease.
BP6	Not met	ClinVar classification is Uncertain Significance (1-star), not benign. BP6 requires a reputable source to report the variant as benign, which is not met.	clinvar
BP7	N/A	NM_016507.4:c.1601C>T is a missense variant (p.Ser534Phe), not a synonymous variant. BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.