CDK12 c.162del, p.(Leu55TrpfsTer2)

28 criteria with recorded statuses: 3 met · 15 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

Evidence considered

• Frameshift variant has no missense comparator at this residue

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_016507.4:c.162del is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PP5 N/APP5 requires a ClinVar assertion from a reputable source. NM_016507.4:c.162del is absent from ClinVar. Details ▾Hide ▴

Evidence considered

• Variant absent from ClinVar

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. NM_016507.4:c.162del is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ABP6 requires a ClinVar assertion from a reputable source. NM_016507.4:c.162del is absent from ClinVar. Details ▾Hide ▴

Evidence considered

• Variant absent from ClinVar

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_016507.4:c.162del is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 relies on ClinVar assertions from a reputable source. This variant is absent from ClinVar; there is no assertion to evaluate. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene

CDK12

Transcript

NM_016507.4

Coding (HGVS c.)

NM_016507.4:c.162del

Protein (HGVS p.)

NP_057591.2:p.(Leu55TrpfsTer2)

GRCh38

chr17:39462229 TG>T

GRCh37

chr17:37618482 TG>T

Gene diagram

Every interpreted variant in CDK12, mapped onto the exon structure of NM_016507.4. Select a row to find it on the plot.

Statements

SpliceAI and Pangolin

Other predictors

REVEL

Not available

BayesDel

Not available

How the predictions were used

PP3 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. Details ▾Hide ▴

Evidence considered

• SpliceAI max delta score = 0.02 (no splice impact predicted)
• REVEL and BayesDel not applicable to non-SNV variants

Still missing

• No in silico prediction tools applicable to frameshift variants

Sources

spliceai ↗

BP4 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. Details ▾Hide ▴

Evidence considered

• SpliceAI max delta = 0.02 (neutral
• not benign-predictive)
• No REVEL/BayesDel available for non-SNV variant

Still missing

• No in silico tools applicable for benign prediction of frameshift variants

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_016507.4:c.162del is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

• Integrated genomic analyses of ovarian carcinoma.

  The TCGA integrated genomic analysis of 316 high-grade serous ovarian carcinomas identified CDK12 as one of nine recurrently mutated genes. Five of nine CDK12 mutations were nonsense or indel, suggesting loss of function; four missense mutations (R882L, Y901C, K975E, L996F) clustered in the kinase domain.

  Does not name this variant
  PMID 21720365 ↗
  Quoted passage

  Five of the nine CDK12 mutations were either nonsense or indel, suggesting potential loss of function, while the four missense mutations (R882L, Y901C, K975E, and L996F) were clustered in its protein kinase domain.

  Results, Mutation analysis; Table 2

• 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.

  Ovarian cancer-associated CDK12 mutations disable catalytic activity of the kinase. Frameshift or point mutations introducing premature stop codons preceding the kinase domain produce truncated proteins without kinase activity. CDK12 depletion reduced BRCA1 levels and disrupted homologous recombination repair in ovarian cancer cell lines. The kinase-dead K756R mutant and tumor-associated G909R mutant failed to restore RAD51 foci formation.

  Does not name this variant
  PMID 24554720 ↗
  Quoted passage

  In one group, frameshift or point mutations introduce premature stop codons that precede the kinase domain such that the predicted protein would not have kinase activity (Fig. 1A).

  Figure 1A; Results, paragraph 1

• Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex.

  CDK12 mutations in high-grade serous ovarian carcinoma prevent formation of the Cdk12/CycK complex or abrogate kinase activity. Examined mutations include L122fs4*, Q602*, W719*, E928fs27*, R882L, Y901C, K975E, L996F, and T1014_Q1016del. Most mutations either ablated CycK binding or inactivated the kinase. Patient samples with CDK12 mutations showed downregulation of HR DNA repair genes including ATM, ATR, CHEK1, FANCI, MDC1, and RAD51D.

  Does not name this variant
  PMID 25712099 ↗
  Quoted passage

  Among the nonsense mutations, the L122fs*4 and Q602* are the most drastic, since they yield the mutant Cdk12 proteins without most predicted regions.

  Results, Figures 1-6; Supplementary Table S1

• Comprehensive Immune Profiling of Lung Adenocarcinomas Reveals Four Immunosubtypes with Plasma Cell Subtype a Negative Indicator.

  Comprehensive immune profiling of 111 lung adenocarcinomas identifies four immunosubtypes based on infiltrating immune cell profiles. The plasma cell subtype is an independent negative prognostic factor. No CDK12 mutations or variant-level data are discussed.

  Does not name this variant
  PMID 26787825 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

• ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_016507.4%3Ac.162del
• gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37618482-TG-T?dataset=gnom…
• gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39462229-TG-T?dataset=g…
• gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39462229-TG-T
• SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016507.4%3Ac.162d…
• OncoKB ↗www.oncokb.org/gene/CDK12/L55Wfs*2
• COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK12+c.162del
• Cancer hotspots ↗www.cancerhotspots.org/

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.