About CDK12
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK12 c.4099G>A, p.(Val1367Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at extremely low frequency in gnomAD v4.1 (1/1,614,182 alleles, AF=6.2×10⁻⁷, highest subpopulation AF=1.33×10⁻⁵ in African/African American). The total allele frequency is well below the 0.1% PM2 threshold. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence consistently predict no damaging effect: REVEL score 0.092 (tolerated, well below the ~0.5 threshold for pathogenicity), BayesDel score −0.587 (benign range), and SpliceAI max delta score 0.02 (no predicted splicing impact). Three independent in silico tools concur on a benign interpretation.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,182 alleles
gnomAD v4.1: 1 / 1,614,182 alleles. Recorded AF 6.19509e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV71001028, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_016507.4:c.4099G>A (p.Val1367Ile) in CDK12 meets PM2 at supporting level: absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (1/1,614,182 alleles, AF=6.2×10⁻⁷).
BP4 is met at supporting level: multiple computational tools consistently predict a benign effect, including REVEL 0.092, BayesDel −0.587, and SpliceAI max delta 0.02.
PVS1 is not applicable (missense substitution). All other assessed criteria (PS1–PS5, PM1, PM5–PM6, PP1–PP5, BA1, BS1–BS4, BP1–BP2, BP5–BP7) are not met due to absence of variant-specific clinical, functional, segregation, or de novo evidence.
One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. Under generic ACMG/AMP 2015 combination rules, this yields conflicting evidence — insufficient to classify as pathogenic, likely pathogenic, likely benign, or benign. The overall classification is Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at extremely low frequency in gnomAD v4.1 (1/1,614,182 alleles, AF=6.2×10⁻⁷, highest subpopulation AF=1.33×10⁻⁵ in African/African American). The total allele frequency is well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD-Canada v1.0
- gnomAD v4.1: 1/1
- 614
- 182 alleles (AF=6.2e-07
- 0 homozygotes)
- Highest subpopulation AF: African/African American 1.33e-05 (1/75
- 038 alleles)
Sources
BP4 SupportingMultiple lines of computational evidence consistently predict no damaging effect: REVEL score 0.092 (tolerated, well below the ~0.5 threshold for pathogenicity), BayesDel score −0.587 (benign range), and SpliceAI max delta score 0.02 (no predicted splicing impact). Three independent in silico tools concur on a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.092 (tolerated/benign — well below ~0.5 pathogenic threshold)
- BayesDel: -0.587 (benign)
- SpliceAI max delta: 0.02 (no predicted splice alteration)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternative nucleotide change at c.4099 resulting in p.Val1367Ile has been established as pathogenic. No same-amino-acid comparator data available. Details ▾Hide ▴
Evidence considered
- No pathogenic same-amino-acid comparators identified
Still missing
- No ClinVar or literature evidence for a different nucleotide change producing V1367I with a pathogenic classification
PS2 No de novo observation reported for this variant in any source, and no paternity/maternity confirmation data are available. Details ▾Hide ▴
Evidence considered
- No de novo data available
Still missing
- No de novo testing or trio data
PS3 No well-established in vitro or in vivo functional studies demonstrate a damaging effect for NM_016507.4:c.4099G>A (p.Val1367Ile). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. No variant-specific functional studies were identified in the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: unknown oncogenic effect
- no variant-specific functional data
- no functional studies found in literature
Still missing
- No functional data (enzymatic assay
- cellular model
- or animal model) available for this variant
Sources
PS4 No case-control data demonstrate significantly increased prevalence of this variant in affected individuals versus controls. Observed once in COSMIC (somatic cancer, COSV71001028), but somatic occurrence does not satisfy germline PS4. Details ▾Hide ▴
Evidence considered
- Single somatic observation in COSMIC
- absent from gnomAD v2.1
- single allele in gnomAD v4.1 (AF=6.2e-07)
Still missing
- No case-control or cohort prevalence data
Sources
PM1 Residue Val1367 is located in the C-terminal domain of CDK12 (amino acid 1367 of 1490), well outside the kinase domain (approximately residues 700–1050). Hotspot analysis does not identify this residue as a statistically significant mutational hotspot. No functional domain critical to disease pathogenesis has been established at this position. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot
- C-terminal region outside kinase domain
Still missing
- No established functional domain at residue 1367
PM6 No de novo observation with unconfirmed parentage has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available
Still missing
- No de novo testing data
PP1 No cosegregation data with disease in multiple affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data
Still missing
- No family studies or segregation analysis
PP2 CDK12 disease mechanism involves loss-of-function variants (truncating, splice), not predominantly missense variation. There is insufficient evidence that CDK12 has a low rate of benign missense variation and that missense variants are a common mechanism of disease, as required for PP2. Details ▾Hide ▴
Evidence considered
- CDK12 disease mechanism primarily loss-of-function
- insufficient evidence for PP2 missense constraint
Still missing
- No gene-level missense constraint metric (e.g.
- Z-score
- gnomAD missense constraint)
Sources
pvs1_gene_context
PP3 Multiple in silico tools consistently predict a benign or tolerated effect: REVEL score 0.092 (well below the ~0.5 pathogenic threshold), BayesDel score −0.587 (benign range), and SpliceAI max delta 0.02 (no predicted splice impact). This evidence supports BP4 rather than PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.092 (tolerated/benign)
- BayesDel: -0.587 (benign)
- SpliceAI max delta: 0.02 (no splice impact)
Sources
PP4 No clinical phenotype data are available for the individual(s) carrying this variant. The variant cannot be assessed for phenotype specificity to CDK12-associated disease. Details ▾Hide ▴
Evidence considered
- No phenotype data available
Still missing
- No proband phenotype or clinical history
PP5 No reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance (1 submitter, criteria provided, single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided
- single submitter (Ambry Genetics)
Sources
BA1 The allele frequency is 6.2×10⁻⁷ (0.00006%), far below the 1% BA1 threshold. This variant is not common in any population. Details ▾Hide ▴
BS1 The allele frequency is 6.2×10⁻⁷ (0.00006%), well below the 0.3% BS1 threshold. This variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
BS2 No observation in a healthy adult individual has been documented for a fully penetrant disorder context; clinical data for the single gnomAD carrier are unavailable. Details ▾Hide ▴
Evidence considered
- Single gnomAD carrier
- no clinical phenotype of that individual available
Still missing
- No healthy control genotype-phenotype data
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. Although in silico predictors suggest a benign effect, computational evidence alone is insufficient to meet BS3. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies available
Still missing
- No functional assay data (e.g.
- kinase activity
- cellular proliferation
- animal model)
BS4 No segregation data are available to demonstrate lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data
Still missing
- No family segregation analysis
BP1 While CDK12 loss-of-function variants are associated with disease, there is insufficient evidence that truncating variants are the sole or overwhelmingly predominant disease mechanism such that any missense variant can be considered likely benign under BP1. Details ▾Hide ▴
Evidence considered
- CDK12 LoF mechanism supported but insufficient to assert BP1 for all missense variants
Still missing
- No comprehensive CDK12 variant spectrum analysis to establish truncating predominance
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a pathogenic CDK12 variant (for a dominant disorder) or in cis with a pathogenic variant has been reported. Details ▾Hide ▴
Evidence considered
- No phase data available
Still missing
- No phasing or co-occurrence data
BP5 No alternate molecular basis for disease has been identified in an individual carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data
Still missing
- No data on co-occurring pathogenic variants in other genes
BP6 No reputable source has classified this variant as benign. ClinVar reports a single submission of Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- no benign classification from any source
Sources
PS5 While CDK12 has been associated with prostate cancer in the germline context, no specific evidence links this variant to a well-established disease phenotype meeting the PS5 standard of a reputable source reporting it as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- single submitter
Still missing
- No reputable source has classified this variant as pathogenic
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_016507.4:c.4099G>A is a missense substitution (p.Val1367Ile), not a null variant (nonsense, frameshift, or canonical splice ±1,2). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution
- not in a null-variant bucket
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo pathogenic variant at the same residue (Val1367) was identified to support PM5 comparator analysis. The automated PM5 candidate harvest returned zero candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic comparator candidates identified
Sources
pm5_candidates
BP7 N/ANM_016507.4:c.4099G>A is a missense variant (p.Val1367Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- Missense variant — BP7 is for synonymous variants only
Identifiers
- Gene
- CDK12
- Transcript
- NM_016507.4
- Coding (HGVS c.)
- NM_016507.4:c.4099G>A
- Protein (HGVS p.)
- NP_057591.2:p.(Val1367Ile)
- GRCh38
- chr17:39530942 G>A
- GRCh37
- chr17:37687195 G>A
- ClinVar
- 3999469
- COSMIC
- COSV71001028
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.
CDK12NM_016507.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in CDK12
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,614,182 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,182 alleles · 0 hom
| African/African American1 / 75,038 | 1.3e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19509e-07; MAF= 0.00006%, 1/1614182 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33266e-05; MAF= 0.00133%, 1/75038 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.092
- BayesDel
- -0.587
How the predictions were used
BP4 SupportingMultiple lines of computational evidence consistently predict no damaging effect: REVEL score 0.092 (tolerated, well below the ~0.5 threshold for pathogenicity), BayesDel score −0.587 (benign range), and SpliceAI max delta score 0.02 (no predicted splicing impact). Three independent in silico tools concur on a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.092 (tolerated/benign — well below ~0.5 pathogenic threshold)
- BayesDel: -0.587 (benign)
- SpliceAI max delta: 0.02 (no predicted splice alteration)
Sources
PP3 Multiple in silico tools consistently predict a benign or tolerated effect: REVEL score 0.092 (well below the ~0.5 pathogenic threshold), BayesDel score −0.587 (benign range), and SpliceAI max delta 0.02 (no predicted splice impact). This evidence supports BP4 rather than PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.092 (tolerated/benign)
- BayesDel: -0.587 (benign)
- SpliceAI max delta: 0.02 (no splice impact)
Sources
BP7 N/ANM_016507.4:c.4099G>A is a missense variant (p.Val1367Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- Missense variant — BP7 is for synonymous variants only
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.092. BayesDel score = -0.587193.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,182 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3999469/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37687195-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39530942-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39530942-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016507.4%3Ac.4099…
- OncoKB ↗www.oncokb.org/gene/CDK12/V1367I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=159087329
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19509e-07; MAF= 0.00006%, 1/1614182 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33266e-05; MAF= 0.00133%, 1/75038 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3999469)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.092. BayesDel score = -0.587193.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV71001028, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.