Variant classification summary

NM_016507.4:c.162del

CDK12 · NP_057591.2:p.(Leu55TrpfsTer2) · NM_016507.4

GRCh37: chr17:37618482 TG>T · GRCh38: chr17:39462229 TG>T

Gene: CDK12 Transcript: NM_016507.4

Final call

Likely Pathogenic

PVS1 strong PM1 supporting PM2 supporting

Variant details

Gene

CDK12

Transcript

NM_016507.4

Protein

NP_057591.2:p.(Leu55TrpfsTer2)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_016507.4:c.162del (p.Leu55TrpfsTer2) is a frameshift variant in CDK12 predicted to undergo nonsense-mediated decay, meeting PVS1 at strong strength.

2

The frameshift at codon 55 truncates the protein at position 56, removing the well-characterized CDK12 kinase domain (aa 719-1051), meeting PM1 at supporting strength.

3

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.

4

No variant-specific functional studies, de novo reports, segregation data, or ClinVar entries exist for this variant. OncoKB classifies this variant as Likely Oncogenic in a somatic context.

5

Applying the ACMG/AMP 2015 classification rules: PVS1 (strong) + PM1 (supporting) + PM2 (supporting) yields Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	NM_016507.4:c.162del is a frameshift variant predicted to cause premature termination at codon 56 (p.Leu55TrpfsTer2) in exon 1 of 14, with predicted nonsense-mediated decay. CDK12 loss of function is established as a germline disease mechanism. Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift variants with predicted NMD in genes where LoF is a known disease mechanism qualify for PVS1 at strong strength.	pvs1_generic_framework gnomad_v2 gnomad_v4
PS1	N/A	PS1 applies to nucleotide substitutions at a position where a different pathogenic substitution has been previously reported. This variant is a single-nucleotide deletion causing a frameshift, not a nucleotide substitution.
PS2	Not met	No de novo data are available for this variant. No publications report de novo occurrence of NM_016507.4:c.162del.
PS3	Not met	No variant-specific functional data exist for NM_016507.4:c.162del. The four publications reviewed discuss CDK12 gene-level functions and characterize other CDK12 mutations (missense and truncating variants in the kinase domain), but none tested or reported functional data for this specific variant. Domain-level inference from characterization of other CDK12 mutations does not satisfy PS3's requirement for variant-specific functional evidence.
PS4	Not met	No case-control or prevalence data are available for NM_016507.4:c.162del. The variant is absent from population databases, and no affected vs. control enrichment data exist.
PS5	N/A	PS5 relies on ClinVar assertions from a reputable source. This variant is absent from ClinVar; there is no assertion to evaluate.
PM1	Met	NM_016507.4:c.162del produces a frameshift at codon 55 (p.Leu55TrpfsTer2), truncating the protein at position 56 and removing the well-characterized CDK12 kinase domain (aa 719–1051) and all other functional regions. CDK12 kinase domain function in DNA damage response and homologous recombination repair is established in the literature. Applied at supporting strength to avoid double-counting with PVS1.	oncokb
PM2	Met	NM_016507.4:c.162del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the PM2 allele frequency threshold of <0.1% for a non-VCEP assessment.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to non-frameshift in-frame deletions/insertions. NM_016507.4:c.162del is a single-nucleotide deletion causing a frameshift; PVS1 addresses the null variant effect.
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. NM_016507.4:c.162del is a frameshift deletion with no missense comparator. Candidate harvesting was attempted but no same-residue comparators were identified.	pm5_candidates
PM6	Not met	No de novo data are available for NM_016507.4:c.162del. No publication reports a de novo occurrence of this variant.
PP1	Not met	No segregation data are available for NM_016507.4:c.162del.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_016507.4:c.162del is a frameshift deletion.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not available as they apply only to single-nucleotide substitutions. No in silico tool supports a pathogenic effect for this variant.	spliceai
PP4	Not met	No patient-specific phenotype data are available for this case. The variant has been flagged by OncoKB as Likely Oncogenic in a somatic context, but no germline phenotype correlation data exist.
PP5	N/A	PP5 requires a ClinVar assertion from a reputable source. NM_016507.4:c.162del is absent from ClinVar.
BA1	Not met	NM_016507.4:c.162del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1%, which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_016507.4:c.162del is absent from gnomAD population databases. BS1 requires an allele frequency >0.3% for non-VCEP assessment, which is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation in healthy adult controls are available. BS2 cannot be applied without evidence that the variant has been observed in a healthy adult.
BS3	Not met	No functional data are available demonstrating a benign or neutral effect for NM_016507.4:c.162del. The publications reviewed characterize CDK12 loss-of-function effects as damaging, not benign.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available.
BP1	N/A	BP1 applies to missense variants where a different pathogenic missense change at the same position is known. NM_016507.4:c.162del is a frameshift deletion.
BP2	Not met	No data are available on observation of NM_016507.4:c.162del in trans with a known pathogenic variant in CDK12.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. NM_016507.4:c.162del is a frameshift deletion.
BP4	Not met	SpliceAI predicts no significant splice impact (max delta = 0.02), but this is neutral rather than benign. No in silico tool provides a benign prediction for this frameshift variant. BP4 requires positive in silico evidence of a benign effect.	spliceai
BP5	Not met	No data are available demonstrating an alternate molecular basis for disease in a case harboring NM_016507.4:c.162del.
BP6	N/A	BP6 requires a ClinVar assertion from a reputable source. NM_016507.4:c.162del is absent from ClinVar.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_016507.4:c.162del is a frameshift deletion.

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