About CDK12
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK12 c.86G>C, p.(Ser29Thr)
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
NM_016507.4:c.86G>C is absent from gnomAD v2.1 and v4.1, consistent with a population frequency below 0.1% (PM2).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of in silico evidence predict a benign effect: REVEL score 0.176 (below pathogenic threshold), BayesDel score -0.320 (negative, benign range), and SpliceAI max delta 0.00 (no predicted splicing impact).
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 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.86G>C (p.Ser29Thr) is a missense variant in CDK12 absent from population databases (gnomAD v2.1 and v4.1), supporting PM2 at supporting strength.
Multiple in silico predictors (REVEL 0.176, BayesDel -0.320, SpliceAI 0.00) support a benign effect, meeting BP4 at supporting strength.
No functional studies, case-control data, segregation data, de novo reports, ClinVar classifications, or same-residue pathogenic comparators were identified for this variant.
The variant does not fall within a known functional domain or mutational hotspot, and PVS1 is not applicable as this is a missense substitution.
Overall, PM2 (supporting) and BP4 (supporting) are the only criteria met, yielding a classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules — PM2 and BP4 with equal supporting-level evidence in opposing directions do not reach pathogenic or likely benign thresholds.
No criteria match.
Met · 2
PM2 SupportingNM_016507.4:c.86G>C is absent from gnomAD v2.1 and v4.1, consistent with a population frequency below 0.1% (PM2). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- absent from gnomAD v4.1 (exomes).
Sources
BP4 SupportingMultiple lines of in silico evidence predict a benign effect: REVEL score 0.176 (below pathogenic threshold), BayesDel score -0.320 (negative, benign range), and SpliceAI max delta 0.00 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL 0.176 (benign range)
- BayesDel -0.320 (benign range)
- SpliceAI 0.00 (no splicing impact).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No previously established pathogenic variant at the same amino acid position (p.Ser29) has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no same-residue pathogenic comparator identified.
Sources
PS2 No de novo data are available for this variant; no reports of confirmed parentage with this variant absent from both parents were identified. Details ▾Hide ▴
Evidence considered
- No de novo evidence found in ClinVar
- literature
- or case materials.
Still missing
- De novo testing data not available.
PS3 No functional studies were identified for this variant or for a systematically characterized range that includes p.Ser29. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data
- no systematic range characterization (tiling/saturation/truncation series) found in literature.
Still missing
- No functional studies available for NM_016507.4:c.86G>C.
Sources
PS4 No case-control studies or cohort data demonstrating enrichment of this variant in affected individuals versus controls were identified. Details ▾Hide ▴
Evidence considered
- No case-control or cohort enrichment data available.
Still missing
- No case-control data for this variant.
PM1 Residue p.Ser29 lies in the N-terminal region of CDK12, far upstream of the kinase domain (residues ~720–980), and is not within a well-characterized critical functional domain. This position is not a statistically significant mutational hotspot (cancerhotspots.org). Details ▾Hide ▴
Evidence considered
- No significant hotspot at residue 29
- N-terminal region not established as a critical functional domain.
Sources
PM5 No pathogenic variant at the same amino acid residue (p.Ser29) with a different missense change was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting found zero same-residue comparator variants in ClinVar.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo event has been reported for this variant with confirmed parentage. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- De novo testing data not available.
PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No segregation analysis data identified.
Still missing
- No family segregation data available.
PP2 Insufficient data to confirm that CDK12 has a low rate of benign missense variation and that missense variants are a common mechanism of disease. HCI prior score is not available for this gene. Details ▾Hide ▴
Evidence considered
- HCI prior not available for CDK12
- insufficient population and disease-mechanism data to apply PP2.
Still missing
- No gene-level missense constraint data (HCI prior).
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold), BayesDel score -0.320 (negative), and SpliceAI max delta 0.00 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL 0.176 (below pathogenic threshold)
- BayesDel -0.320 (benign range)
- SpliceAI 0.00 (no splicing impact).
Sources
PP4 No specific phenotype or clinical data are available for the individual carrying this variant. Details ▾Hide ▴
Evidence considered
- No phenotype data provided.
Still missing
- Phenotype information not available.
PP5 This variant is absent from ClinVar; no pathogenic classification from a reputable source is available. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available.
Sources
BA1 NM_016507.4:c.86G>C is absent from population databases; the allele frequency does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- allele frequency 0% does not meet BA1 >1% threshold.
Sources
BS1 The variant is absent from population databases; the allele frequency does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- allele frequency 0% does not meet BS1 >0.3% threshold.
Sources
BS2 No data are available on healthy adult homozygotes or hemizygotes for this variant. Details ▾Hide ▴
Evidence considered
- No homozygous or hemizygous counts in population databases
- no control data.
Still missing
- No homozygote data available.
BS3 No functional studies demonstrating no deleterious effect have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies showing no deleterious effect
- OncoKB reports unknown oncogenic effect.
Still missing
- No benign functional data available.
BS4 No segregation data are available to demonstrate lack of cosegregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation data available.
BP1 CDK12 germline disease mechanism is not exclusively mediated by truncating variants; both missense and truncating variants have been reported in association with prostate cancer. Insufficient evidence to apply BP1. Details ▾Hide ▴
Evidence considered
- CDK12 disease mechanism includes both missense and truncating variants
- BP1 requires primarily truncating mechanism.
BP2 No data on co-occurrence of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
BP5 No alternate molecular basis for disease has been identified in the case to suggest this variant is not causative. Details ▾Hide ▴
Evidence considered
- No alternate genetic cause identified in case materials.
Still missing
- Case phenotype and alternate genetic findings not available.
BP6 This variant is absent from ClinVar; no benign classification from a reputable source is available. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable benign classification available.
Sources
PS5 No previously established pathogenic variant at the same amino acid position (p.Ser29) regardless of nucleotide change has been identified. Details ▾Hide ▴
Evidence considered
- No same-amino-acid pathogenic variant identified in ClinVar or literature.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_016507.4:c.86G>C is a missense variant (p.Ser29Thr) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant classified as missense substitution
- not eligible for generic PVS1 null-variant framework.
Sources
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant; CDK12-associated disease is not established as recessive. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions in non-repeat regions; this is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact; NM_016507.4:c.86G>C is a missense variant (p.Ser29Thr). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous variants.
Identifiers
- Gene
- CDK12
- Transcript
- NM_016507.4
- Coding (HGVS c.)
- NM_016507.4:c.86G>C
- Protein (HGVS p.)
- NP_057591.2:p.(Ser29Thr)
- GRCh38
- chr17:39462157 G>C
- GRCh37
- chr17:37618410 G>C
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDK12
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.176
- BayesDel
- -0.320
How the predictions were used
BP4 SupportingMultiple lines of in silico evidence predict a benign effect: REVEL score 0.176 (below pathogenic threshold), BayesDel score -0.320 (negative, benign range), and SpliceAI max delta 0.00 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL 0.176 (benign range)
- BayesDel -0.320 (benign range)
- SpliceAI 0.00 (no splicing impact).
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold), BayesDel score -0.320 (negative), and SpliceAI max delta 0.00 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL 0.176 (below pathogenic threshold)
- BayesDel -0.320 (benign range)
- SpliceAI 0.00 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact; NM_016507.4:c.86G>C is a missense variant (p.Ser29Thr). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.176. BayesDel score = -0.320226.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_016507.4%3Ac.86G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37618410-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39462157-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39462157-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016507.4%3Ac.86G%…
- OncoKB ↗www.oncokb.org/gene/CDK12/S29T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK12+c.86G%3EC
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.176. BayesDel score = -0.320226.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.