About CDK12
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK12 c.2351G>A, p.(Arg784Gln)
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 present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00109% (3/275,404 alleles), gnomAD v4.1 AF = 0.00112% (18/1,609,482 alleles), and is absent from gnomAD-Canada. The highest subpopulation frequency is 0.028% in gnomAD v2.1 Remaining individuals, well below the 0.1% threshold for PM2.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.075 (strongly benign, far below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta score 0.01 (no predicted splicing alteration).
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 benign; 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
18 / 1,609,482 alleles
gnomAD v4.1: 18 / 1,609,482 alleles. Recorded AF 1.11837e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.08931e-05; MAF= 0.00109%, 3/275404 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000281452; MAF= 0.02815%, 2/7106 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV104713462, 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.
27 criteria with recorded statuses: 2 met · 10 not met · 8 not assessed · 7 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.2351G>A (p.Arg784Gln) in CDK12 is a missense variant absent from ClinVar and present at extremely low frequency in population databases (gnomAD v2.1: 3/275,404 alleles, AF 0.00109%; gnomAD v4.1: 18/1,609,482 alleles, AF 0.00112%), meeting PM2 at supporting strength.
Multiple computational predictors support a benign effect: REVEL score 0.075 (strongly benign), BayesDel score −0.516897 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact), meeting BP4 at supporting benign strength.
No functional studies, de novo observations, segregation data, case-control data, or ClinVar classifications were available to support additional pathogenic or benign criteria.
The variant is observed once somatically in COSMIC (COSV104713462) but this does not contribute to germline ACMG/AMP classification.
The supporting pathogenic evidence (PM2) is balanced by supporting benign evidence (BP4). No other criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00109% (3/275,404 alleles), gnomAD v4.1 AF = 0.00112% (18/1,609,482 alleles), and is absent from gnomAD-Canada. The highest subpopulation frequency is 0.028% in gnomAD v2.1 Remaining individuals, well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 3/275
- 404 alleles (AF 0.00109%)
- gnomAD v4.1: 18/1
- 609
- 482 alleles (AF 0.00112%)
- absent from gnomAD-Canada
- no homozygotes
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.075 (strongly benign, far below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta score 0.01 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL 0.075 (strongly benign)
- BayesDel −0.517 (benign)
- SpliceAI max delta 0.01 (no splice impact)
Sources
Not met · 10 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (p.Arg784Gln) has been reported. This variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no established pathogenic variant at this residue
Sources
PS3 No well-established in vitro or in vivo functional studies demonstrate a damaging effect. OncoKB reports unknown oncogenic effect for this variant. REVEL (0.075) and BayesDel (−0.517) predict benign, and no published functional assays were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: unknown oncogenic effect
- REVEL 0.075 (benign)
- BayesDel −0.517 (benign)
- no functional studies identified
Still missing
- No published functional studies for this variant
Sources
PM1 Residue 784 does not lie within a statistically significant mutational hotspot, and the variant is not listed in the Cancer Hotspots database. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot
- exact variant not listed in Cancer Hotspots
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. CDK12 germline disease association is primarily through prostate cancer susceptibility, not a well-characterized Mendelian disorder with established missense constraint metrics. Insufficient evidence to apply PP2. Details ▾Hide ▴
Evidence considered
- CDK12 is not established as a gene where missense variants are a common mechanism of a well-defined Mendelian disease with low benign missense rate
Still missing
- No gene-level missense constraint metric (e.g.
- Z-score) available
- HCI prior not supported
PP3 Multiple computational tools predict a benign effect: REVEL score 0.075 (strongly benign, well below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact). These do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.075 (benign)
- BayesDel −0.517 (benign)
- SpliceAI max delta 0.01 (no splice impact)
Sources
BA1 The maximum population allele frequency (0.028% in gnomAD v2.1 Remaining individuals) is far below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- Maximum subpopulation AF 0.028% in gnomAD v2.1
- far below 1% BA1 threshold
Sources
BS1 The maximum population allele frequency (0.028% in gnomAD v2.1 Remaining individuals) is below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- Maximum subpopulation AF 0.028% in gnomAD v2.1
- below 0.3% BS1 threshold
Sources
BS2 No homozygous individuals have been observed in gnomAD v2.1, v4.1, or gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Homozygote count = 0 in all population databases
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect. While in silico predictors favor benign (REVEL 0.075, BayesDel −0.517), these do not constitute well-established functional evidence per ACMG/AMP guidelines. Details ▾Hide ▴
Evidence considered
- REVEL 0.075 (benign)
- BayesDel −0.517 (benign)
- insufficient to meet BS3 threshold without well-established functional assays
Still missing
- No direct functional assay data for this variant
Sources
revelbayesdel
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. While CDK12 loss of function is a supported germline disease mechanism, the available literature does not establish that the disease is caused primarily by truncating variants; both missense and truncating DDR gene variants are reported in prostate cancer cohorts. Insufficient evidence to confidently apply BP1. Details ▾Hide ▴
Evidence considered
- CDK12 LOF mechanism supported but insufficient evidence that disease is primarily caused by truncating variants
Still missing
- No established truncating-only disease mechanism for CDK12 germline disorders
Sources
pvs1_gene_context
Not assessed · 8 · no assessment recorded
PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
- No parental or de novo testing data available
PS4 No case-control or prevalence data comparing affected vs. general population are available for this variant. Details ▾Hide ▴
Still missing
- No case-control or prevalence data available
PM6 No de novo data available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
PP4 No patient phenotype information was provided for this case. Details ▾Hide ▴
Still missing
- No patient phenotype or clinical context available
BS4 No segregation data available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No data available regarding observation in trans with a pathogenic variant. Details ▾Hide ▴
Still missing
- No trans-phase data available
BP5 No data available regarding an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_016507.4:c.2351G>A is a missense variant (p.Arg784Gln). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 framework (PMC6185798) is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo pathogenic missense comparator variants at the same residue (Arg784) were identified in ClinVar; PM5 candidate harvesting returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- No pathogenic same-residue comparators identified
Sources
pm5_candidates
PP5 N/AThis variant is absent from ClinVar; no reputable source reports it as pathogenic. Details ▾Hide ▴
BP3 N/AIn-frame deletions/insertions in repetitive region not relevant to this substitution variant. Details ▾Hide ▴
Evidence considered
- Skipped: variant is a substitution
- not an in-frame indel in a repetitive region
BP6 N/AThis variant is absent from ClinVar; no reputable source reports it as benign. Details ▾Hide ▴
BP7 N/AThis is a missense variant (c.2351G>A, p.Arg784Gln), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 not applicable
PS5 N/AThis variant is absent from ClinVar; no reputable source reports it as pathogenic. Details ▾Hide ▴
Identifiers
- Gene
- CDK12
- Transcript
- NM_016507.4
- Coding (HGVS c.)
- NM_016507.4:c.2351G>A
- Protein (HGVS p.)
- NP_057591.2:p.(Arg784Gln)
- GRCh38
- chr17:39494626 G>A
- GRCh37
- chr17:37650879 G>A
- COSMIC
- COSV104713462
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
18 / 1,609,482 alleles
AF 1.12e-05 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1
3 / 275,404 alleles
AF 1.09e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.1e-05 · 18 / 1,609,482 alleles · 0 hom · FAF 2.5e-06
| European (Finnish)10 / 63,854 | 0.00016 |
| Remaining individuals1 / 62,320 | 1.6e-05 |
| European (non-Finnish)7 / 1,177,366 | 5.9e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.1e-05 · 3 / 275,404 alleles · 0 hom
| Remaining individuals2 / 7,106 | 0.00028 |
| European (non-Finnish)1 / 124,794 | 8e-06 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.11837e-05; MAF= 0.00112%, 18/1609482 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000156607; MAF= 0.01566%, 10/63854 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.08931e-05; MAF= 0.00109%, 3/275404 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000281452; MAF= 0.02815%, 2/7106 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.075
- BayesDel
- -0.517
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.075 (strongly benign, far below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta score 0.01 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL 0.075 (strongly benign)
- BayesDel −0.517 (benign)
- SpliceAI max delta 0.01 (no splice impact)
Sources
PP3 Multiple computational tools predict a benign effect: REVEL score 0.075 (strongly benign, well below 0.5 threshold), BayesDel score −0.516897 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact). These do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.075 (benign)
- BayesDel −0.517 (benign)
- SpliceAI max delta 0.01 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.2351G>A, p.Arg784Gln), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 not applicable
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.075. BayesDel score = -0.516897.
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
18 / 1,609,482 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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.2351G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37650879-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39494626-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39494626-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016507.4%3Ac.2351…
- OncoKB ↗www.oncokb.org/gene/CDK12/R784Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=159081604
- 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= 1.11837e-05; MAF= 0.00112%, 18/1609482 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000156607; MAF= 0.01566%, 10/63854 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.08931e-05; MAF= 0.00109%, 3/275404 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000281452; MAF= 0.02815%, 2/7106 alleles, homozygotes = 0).
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 = 0.01). REVEL score = 0.075. BayesDel score = -0.516897.
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; COSV104713462, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.