NM_016507.4:c.2351G>A

CDK12 · NP_057591.2:p.(Arg784Gln) · NM_016507.4

GRCh37: chr17:37650879 G>A · GRCh38: chr17:39494626 G>A

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.(Arg784Gln)

gnomAD AF

1.1183722464743315e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_016507.4:c.2351G>A (p.Arg784Gln) in CDK12 is a missense variant absent from ClinVar and present at extremely low frequency in population databases (gnomAD v2.1: 3/275,404 alleles, AF 0.00109%; gnomAD v4.1: 18/1,609,482 alleles, AF 0.00112%), meeting PM2 at supporting strength.

Multiple computational predictors support a benign effect: REVEL score 0.075 (strongly benign), BayesDel score −0.516897 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact), meeting BP4 at supporting benign strength.

No functional studies, de novo observations, segregation data, case-control data, or ClinVar classifications were available to support additional pathogenic or benign criteria.

The variant is observed once somatically in COSMIC (COSV104713462) but this does not contribute to germline ACMG/AMP classification.

The supporting pathogenic evidence (PM2) is balanced by supporting benign evidence (BP4). No other criteria are met. 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.2351G>A is a missense variant (p.Arg784Gln). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 framework (PMC6185798) is not applicable to this variant class.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Arg784Gln) has been reported. This variant is absent from ClinVar.	clinvar
PS2	Not assessed	No de novo data available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a damaging effect. OncoKB reports unknown oncogenic effect for this variant. REVEL (0.075) and BayesDel (−0.517) predict benign, and no published functional assays were identified.	oncokb revel bayesdel
PS4	Not assessed	No case-control or prevalence data comparing affected vs. general population are available for this variant.
PS5	N/A	This variant is absent from ClinVar; no reputable source reports it as pathogenic.	clinvar
PM1	Not met	Residue 784 does not lie within a statistically significant mutational hotspot, and the variant is not listed in the Cancer Hotspots database.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00109% (3/275,404 alleles), gnomAD v4.1 AF = 0.00112% (18/1,609,482 alleles), and is absent from gnomAD-Canada. The highest subpopulation frequency is 0.028% in gnomAD v2.1 Remaining individuals, well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense comparator variants at the same residue (Arg784) were identified in ClinVar; PM5 candidate harvesting returned no eligible comparators.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. CDK12 germline disease association is primarily through prostate cancer susceptibility, not a well-characterized Mendelian disorder with established missense constraint metrics. Insufficient evidence to apply PP2.
PP3	Not met	Multiple computational tools predict a benign effect: REVEL score 0.075 (strongly benign, well below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact). These do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype information was provided for this case.
PP5	N/A	This variant is absent from ClinVar; no reputable source reports it as pathogenic.	clinvar
BA1	Not met	The maximum population allele frequency (0.028% in gnomAD v2.1 Remaining individuals) is far below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum population allele frequency (0.028% in gnomAD v2.1 Remaining individuals) is below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals have been observed in gnomAD v2.1, v4.1, or gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect. While in silico predictors favor benign (REVEL 0.075, BayesDel −0.517), these do not constitute well-established functional evidence per ACMG/AMP guidelines.	revel bayesdel
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. While CDK12 loss of function is a supported germline disease mechanism, the available literature does not establish that the disease is caused primarily by truncating variants; both missense and truncating DDR gene variants are reported in prostate cancer cohorts. Insufficient evidence to confidently apply BP1.	pvs1_gene_context
BP2	Not assessed	No data available regarding observation in trans with a pathogenic variant.
BP3	N/A	In-frame deletions/insertions in repetitive region not relevant to this substitution variant.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.075 (strongly benign, far below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta score 0.01 (no predicted splicing alteration).	revel bayesdel spliceai
BP5	Not assessed	No data available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	N/A	This variant is absent from ClinVar; no reputable source reports it as benign.	clinvar
BP7	N/A	This is a missense variant (c.2351G>A, p.Arg784Gln), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact.

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.