NM_016507.4:c.2964C>T

CDK12 · NP_057591.2:p.(Phe988=) · NM_016507.4

GRCh37: chr17:37676209 C>T · GRCh38: chr17:39519956 C>T

Gene: CDK12 Transcript: NM_016507.4

Final call

Likely Benign

BS1 strong benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

CDK12

Transcript

NM_016507.4

Protein

NP_057591.2:p.(Phe988=)

gnomAD AF

0.0004430789213414075 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_016507.4:c.2964C>T (p.Phe988=) is a synonymous variant in CDK12. This variant is present in gnomAD at a grpmax filtering allele frequency of 0.798% (v2.1) and 0.781% (v4.1), with an African/African American subpopulation frequency of 0.885%, meeting BS1 at strong benign strength.

The variant is observed in 2 homozygous individuals in gnomAD v2.1 and 4 homozygous individuals in gnomAD v4.1, further supporting that biallelic presence is tolerated in the general population.

SpliceAI predicts no impact on splicing (max delta score 0.02), consistent with a synonymous variant that does not alter the protein product or disrupt normal mRNA processing, meeting BP7 at supporting benign strength.

Computational splicing predictions show no evidence of splice site disruption, meeting BP4 at supporting benign strength.

ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory); however the review status is 1-star (criteria provided, single submitter) and does not independently meet the 3-star expert panel threshold for BP6.

No pathogenic criteria are met. BS1 (strong benign), BP4 (supporting benign), and BP7 (supporting benign) together support a classification of Likely benign per ACMG/AMP 2015 guidelines.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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.2964C>T is a synonymous variant (p.Phe988=) with no predicted impact on splicing (SpliceAI max delta 0.02). PVS1 requires a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion) and does not apply to synonymous substitutions outside the splice consensus.	spliceai pvs1_variant_assessment pvs1_gene_context
PS1	Not met	PS1 requires a different nucleotide change at the same codon producing the same missense change that has been previously classified as pathogenic. This is a synonymous variant (p.Phe988=) and does not produce a missense change.
PS2	Not met	No evidence of de novo occurrence for NM_016507.4:c.2964C>T in any published study or database. No parent-of-origin testing data available.
PS3	Not met	No functional data identified for this synonymous variant. OncoKB lists this variant as 'Unknown Oncogenic Effect' with no associated curated publications. No experimental studies testing NM_016507.4:c.2964C>T were found in the literature.	oncokb
PS4	Not met	No case-control studies demonstrating enrichment of this variant in affected individuals compared to controls. The literature papers associated with this variant via ClinVar are BRCA-focused clinical guidelines (PMID:17392385, 23188549, 24366376, 24366402, 24493721) and a population survey (PMID:24728327) that do not mention CDK12 or this variant. No variant-specific case observations were identified.
PS5	N/A	PS5 requires a different pathogenic missense variant at the same codon. This is a synonymous variant that does not alter the amino acid; the PS5 framework for same-codon comparator variants does not apply.
PM1	Not met	Although CDK12 contains a kinase domain (approximately residues 723-1002) and position 988 falls within the C-terminal region of this domain, this is a synonymous variant (p.Phe988=) with no predicted splice impact (SpliceAI max delta 0.02). The variant does not alter the protein product or disrupt a functional domain. Cancerhotspots.org does not list this residue as a statistically significant hotspot. PM1 requires a variant that alters or disrupts a critical functional domain, which is not the case for a synonymous substitution with no splicing consequences.	spliceai
PM2	Not met	This variant is present in gnomAD population databases at a frequency exceeding the PM2 threshold of <0.1%. In gnomAD v2.1 the variant has a total allele frequency of 0.086% (243/282,676 alleles) and a maximum subpopulation frequency of 0.885% in the African/African American population (221/24,968 alleles, 2 homozygotes); grpmax FAF is 0.798%. In gnomAD v4.1 the variant has 715/1,613,708 alleles (0.044%) with African/African American AF of 0.835% (626/74,982 alleles, 4 homozygotes); grpmax FAF is 0.781%. The grpmax filtering allele frequency in both datasets is well above 0.1%, so PM2 is not met.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires an alternate missense change at the same codon that has been classified as pathogenic. This variant is synonymous (p.Phe988=) and does not produce a missense change, so no comparator missense variant at codon 988 can be evaluated under PM5.	pm5_candidates
PM6	Not met	No evidence of de novo occurrence for NM_016507.4:c.2964C>T. No published reports or database entries document this variant arising de novo with confirmed maternity and paternity.
PP1	Not met	No cosegregation data available for NM_016507.4:c.2964C>T with disease in affected family members.
PP2	N/A	PP2 specifically applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a synonymous variant (p.Phe988=) and does not meet the missense requirement for PP2.
PP3	Not met	In silico prediction tools do not support a deleterious effect. REVEL and BayesDel scores are not available for this variant. SpliceAI predicts no splice impact (max delta score 0.02, well below the 0.2 threshold). No computational evidence supports pathogenicity.	spliceai
PP4	Not met	No evidence that the patient's phenotype or family history is highly specific for CDK12-related disease. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar lists this variant as 'Likely benign' (ClinVar Variation ID 133856) with review status 'criteria provided, single submitter' (1-star). PP5 requires a reputable source (i.e., expert panel with 3-star review status) to have classified the variant as pathogenic. The current review status does not meet the threshold for PP5 application.	clinvar
BA1	Not met	The maximum subpopulation allele frequency in gnomAD is 0.885% in the African/African American population (gnomAD v2.1), with a grpmax FAF of 0.798%. These are below the BA1 threshold of >1.0%. The variant is not common enough to be considered a benign population polymorphism under BA1.	gnomad_v2 gnomad_v4
BS1	Met	The allele frequency of NM_016507.4:c.2964C>T in population databases exceeds the threshold expected for a pathogenic CDK12 variant. In gnomAD v2.1, the variant has a grpmax filtering allele frequency of 0.798% (African/African American subpopulation AF 0.885%) with 2 homozygous individuals. In gnomAD v4.1, the grpmax FAF is 0.781% (African/African American AF 0.835%) with 4 homozygous individuals. These frequencies are well above the BS1 threshold of >0.3% for a rare Mendelian disorder gene, supporting that this variant is too common in the general population to be pathogenic.	gnomad_v2 gnomad_v4
BS2	Not met	Although the variant is observed in 2 homozygous individuals in gnomAD v2.1 and 4 homozygous individuals in gnomAD v4.1, BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age. CDK12 germline variants are associated with adult-onset prostate cancer susceptibility, which is not a fully penetrant early-onset disorder. Under strict ACMG/AMP criteria, the homozygous observations do not satisfy BS2 for a late-onset, incompletely penetrant condition.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a neutral (benign) effect for NM_016507.4:c.2964C>T. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No such studies have been conducted for this synonymous variant.
BS4	Not met	No cosegregation data available demonstrating lack of segregation with disease for NM_016507.4:c.2964C>T. BS4 requires observation of the variant in multiple family members who do not have the disease (non-segregation with disease).
BP1	N/A	BP1 applies to missense variants in a gene where truncating variants are a known mechanism of disease. This is a synonymous variant (p.Phe988=) and does not meet the missense requirement for BP1.
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant in CDK12. BP2 requires observation in trans with a pathogenic variant for a dominantly inherited disorder, or in cis with a pathogenic variant in a recessive disorder.
BP4	Met	Computational evidence predicts no impact on splicing for this synonymous variant. SpliceAI assigns a maximum delta score of 0.02 (well below the 0.2 threshold), with no predicted donor gain, donor loss, acceptor gain, or acceptor loss. This supports a benign interpretation.	spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease. No patient-level data available to assess whether an alternate genetic cause explains the phenotype.
BP6	Not met	ClinVar reports this variant as 'Likely benign' (Variation ID 133856) with review status 'criteria provided, single submitter' (1-star). BP6 requires a reputable source (3-star expert panel review) to have classified the variant as benign. The current 1-star review status does not meet the threshold for BP6 application.	clinvar
BP7	Met	NM_016507.4:c.2964C>T is a synonymous variant (p.Phe988=) with SpliceAI predicting no splice impact (max delta score 0.02). No donor/acceptor gain or loss is predicted. The nucleotide substitution is not at a highly conserved splice consensus position and computational predictions support no effect on splicing. BP7 is met at supporting benign strength.	spliceai

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