NM_016507.4:c.162del (p.Leu55TrpfsTer2) is a frameshift variant in CDK12 predicted to undergo nonsense-mediated decay, meeting PVS1 at strong strength.1 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.2 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.3 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.4 Applying the ACMG/AMP 2015 classification rules: PVS1 (strong) + PM1 (supporting) + PM2 (supporting) yields Likely Pathogenic.5
CDK12
Final classification
Likely Pathogenic
CDK12 c.162del · p.Leu55TrpfsTer2
CDK12
NM_016507.4:c.162del (p.Leu55TrpfsTer2) is a frameshift variant in CDK12 predicted to undergo nonsense-mediated decay, meeting PVS1 at strong strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM1 supporting, PM2 supporting; combination = 1 strong + 2 supporting, which maps to Likely Pathogenic.
Classification rationale
PVS1PM1PM2
Likely Pathogenic
CDK12 c.162del
PVS1 + PM1 + PM2
→
Likely Pathogenic
Gene diagram
· NM_016507.4 · variants mapped to exon structure
CDK12
NM_016507.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
strong
Pathogenic
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.
Frameshift variant p.Leu55TrpfsTer2 with predicted NMDCDK12 LoF established as germline disease mechanism in prostate cancerMANE select transcript NM_016507.4
✓
PM1
supporting
Pathogenic
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.
Frameshift removes CDK12 kinase domain (aa 719-1051) and all downstream functional domainsCDK12 kinase domain is critical for DNA damage response and homologous recombination repair
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional data exist for NM_016507.4:c.162del.
PS4
No case-control or prevalence data are available for NM_016507.4:c.162del.
PM6
No de novo data are available for NM_016507.4:c.162del.
PP1
No segregation data are available for NM_016507.4:c.162del.
PP3
SpliceAI predicts no significant splice impact (max delta score = 0.02).
PP4
No patient-specific phenotype data are available for this case.
Benign
BA1
NM_016507.4:c.162del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_016507.4:c.162del is absent from gnomAD population databases.
BS2
No data on observation in healthy adult controls are available.
BS3
No functional data are available demonstrating a benign or neutral effect for NM_016507.4:c.162del.
BS4
No segregation data demonstrating lack of cosegregation with disease are available.
BP2
No data are available on observation of NM_016507.4:c.162del in trans with a known pathogenic variant in CDK12.
BP4
SpliceAI predicts no significant splice impact (max delta = 0.02), but this is neutral rather than benign.
BP5
No data are available demonstrating an alternate molecular basis for disease in a case harboring NM_016507.4:c.162del.
N/A · 9
PS1 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
24554720 ↗
Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors.
ONCOKB
25712099 ↗
Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex.
ONCOKB
26787825 ↗
Comprehensive Immune Profiling of Lung Adenocarcinomas Reveals Four Immunosubtypes with Plasma Cell Subtype a Negative Indicator.
ONCOKB