About CDK12
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK12 c.3052G>A, p.(Asp1018Asn)
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 in gnomAD population databases at extremely low frequency: v2.1 AF=0.00389% (11/282,794 alleles) and v4.1 AF=0.00242% (39/1,613,882 alleles), with no homozygotes observed. Both frequencies fall well below the 0.1% threshold for PM2 under generic ACMG. Absent from ClinVar, consistent with a rare variant.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.448 (negative/benign prediction), and SpliceAI max delta 0.00 (no predicted splicing impact) collectively indicate no deleterious effect at the protein or splicing level.
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
39 / 1,613,882 alleles
gnomAD v4.1: 39 / 1,613,882 alleles. Recorded AF 2.41653e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88976e-05; MAF= 0.00389%, 11/282794 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000250601; MAF= 0.02506%, 5/19952 alleles, homozygotes = 0); grpmax FAF= 0.00010624.
gnomAD-Canada
Not available in 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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV109735027, 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.
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.3052G>A (p.Asp1018Asn) is a rare missense variant in CDK12 observed in gnomAD at extremely low frequency (v2.1: AF=0.00389%, 11/282,794 alleles; v4.1: AF=0.00242%, 39/1,613,882 alleles), supporting PM2 at supporting strength.
Multiple in silico tools predict no deleterious effect: REVEL score 0.24, BayesDel score -0.448, and SpliceAI max delta 0.00, meeting BP4 at supporting strength.
The variant is absent from ClinVar and no publications mention this specific variant, limiting clinical interpretation to population and computational data.
One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are in conflict. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this pattern does not reach the threshold for Likely Pathogenic or Likely Benign classification. The variant is interpreted as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is present in gnomAD population databases at extremely low frequency: v2.1 AF=0.00389% (11/282,794 alleles) and v4.1 AF=0.00242% (39/1,613,882 alleles), with no homozygotes observed. Both frequencies fall well below the 0.1% threshold for PM2 under generic ACMG. Absent from ClinVar, consistent with a rare variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00389% (11/282
- 794)
- hom=0
- grpmax FAF=0.0106%
- gnomAD v4.1: AF=0.00242% (39/1
- 613
- 882)
- grpmax FAF=0.0058%
- Population frequency below 0.1% PM2 threshold
Sources
BP4 SupportingBP4 requires multiple lines of computational evidence suggesting no impact on the gene product. REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.448 (negative/benign prediction), and SpliceAI max delta 0.00 (no predicted splicing impact) collectively indicate no deleterious effect at the protein or splicing level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.24 (below 0.5 pathogenic threshold)
- BayesDel: -0.448 (negative
- benign prediction)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change resulting in the same amino acid substitution (D1018N) with a known pathogenic classification. No such comparator variant exists in ClinVar or the literature for this residue. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no known pathogenic D1018N comparators via different nucleotide change
Sources
PS2 PS2 requires a de novo observation (maternity and paternity confirmed). No de novo data are available for this variant in any source. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or curated databases
Still missing
- No de novo testing data available
PS3 PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect. No variant-specific functional data exist for NM_016507.4:c.3052G>A. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. No publications mention this variant. In silico predictions (REVEL, BayesDel, SpliceAI) do not constitute functional evidence for PS3. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
- no publications identified with functional data
Still missing
- No functional studies available for this variant
Sources
PS4 PS4 requires a significantly increased prevalence of the variant in affected individuals compared to controls. No case-control or prevalence data are available for this variant. The variant is absent from ClinVar and no publications report its observation in affected individuals. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no case-control or prevalence studies identified
Still missing
- No affected-individual prevalence data available
PM1 PM1 requires the variant to be located in a mutational hotspot or critical well-established functional domain. Residue D1018 lies within the CDK12 kinase domain but is not flagged as a statistically significant hotspot by cancerhotspots.org, and no variant-specific literature evidence establishes this exact residue as a critical functional domain. General kinase domain membership alone, without residue-level hotspot significance, is insufficient for PM1 under generic ACMG. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not statistically significant
- no literature-defined critical functional domain for this specific residue
PM5 PM5 requires a different pathogenic missense variant at the same codon (Asp1018). PM5 candidate harvesting returned no same-residue candidates from ClinVar. No pathogenic variant at codon 1018 with a different amino acid change has been identified. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator variants at codon 1018 identified in ClinVar
Sources
pm5_candidatesclinvar ↗
PM6 PM6 requires a de novo observation without confirmed maternity and paternity. No de novo data are available for this variant in any source. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No de novo testing data available
PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or family data available
Still missing
- No family segregation data available
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While CDK12 has some evidence for a germline disease role in prostate cancer, no missense constraint metric (e.g., Z-score, o/e) is available to establish a low rate of benign missense variation, and the disease mechanism has not been clearly defined as missense-driven. Details ▾Hide ▴
Evidence considered
- Insufficient evidence for low benign missense variation rate in CDK12
Still missing
- No missense constraint metric (Z-score
- o/e) available
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score 0.24 is below the typical pathogenic threshold (0.5), BayesDel score -0.448 is negative (benign prediction), and SpliceAI max delta score is 0.00 (no splice impact). No computational tool predicts a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.24 (below 0.5 pathogenic threshold)
- BayesDel: -0.448 (negative
- benign prediction)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP4 PP4 requires the variant to be observed in a patient with a phenotype highly specific for the gene or with a well-defined syndrome. No patient phenotype data are available for this variant. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available
Still missing
- No phenotypic data associated with this variant
PP5 PP5 requires the variant to be classified as pathogenic by a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory). This variant is absent from ClinVar entirely; no reputable source has classified it. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available
Sources
BA1 BA1 requires an allele frequency >1% in a general population. The highest observed frequency in gnomAD is 0.033% (v4.1 Middle Eastern subpopulation), well below the 1% stand-alone benign threshold. The variant is too rare for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.033% (Middle Eastern)
- Far below 1% BA1 threshold
Sources
BS1 BS1 requires an allele frequency >0.3% in a general population. The highest observed frequency in gnomAD is 0.033% (v4.1 Middle Eastern subpopulation), below the 0.3% strong benign threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.033% (Middle Eastern)
- Below 0.3% BS1 threshold
Sources
BS2 BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age. CDK12 germline variants are associated with adult-onset prostate cancer with reduced penetrance, so observation in healthy adults does not constitute strong evidence of benignity under the BS2 framework. Furthermore, no specific clinical data for the observed carriers are available. Details ▾Hide ▴
Evidence considered
- CDK12 germline disease is adult-onset with reduced penetrance
- BS2 criteria not satisfied
Still missing
- No carrier clinical phenotype data available
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional data exist for this variant. In silico predictions (REVEL 0.24, BayesDel -0.448) are computational, not functional, and do not constitute BS3 evidence. Details ▾Hide ▴
Evidence considered
- No functional studies available for this variant
Still missing
- No functional studies available
BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or family data available
Still missing
- No family segregation data available
BP1 BP1 requires a missense variant in a gene where only truncating variants are the primary known disease mechanism. While CDK12 has evidence for loss-of-function as a disease mechanism, missense variants are also reported in cancer contexts (COSMIC: n=1), and there is insufficient evidence that only truncating variants drive CDK12-related germline disease. Details ▾Hide ▴
Evidence considered
- CDK12 disease mechanism not established as truncating-only
- missense variants also observed in somatic contexts
Still missing
- Unclear whether CDK12 germline disease is exclusively truncation-driven
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such data are available. Details ▾Hide ▴
Evidence considered
- No in trans or in cis observations available
Still missing
- No trans/cis phase data available
BP5 BP5 requires an alternative molecular basis for disease to have been identified in the affected individual. No such data are available for this case. Details ▾Hide ▴
Evidence considered
- No alternative molecular basis reported
Still missing
- No alternative molecular diagnosis data available
BP6 BP6 requires the variant to be classified as benign by a reputable source (e.g., ClinVar expert panel). This variant is absent from ClinVar entirely; no reputable source has classified it as benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source benign classification available
Sources
PS5 PS5 requires a different nucleotide change at the same codon predicted to produce the same missense change, classified as pathogenic by a reputable source. No pathogenic variant at codon 1018 (alternate nucleotide) has been identified in ClinVar. Details ▾Hide ▴
Evidence considered
- No pathogenic comparators at codon 1018 found in ClinVar
- PM5 candidate search returned no results
Sources
clinvar ↗pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice, initiation codon, exon-level deletions). NM_016507.4:c.3052G>A is a missense variant (p.Asp1018Asn) and does not fall into any of the generic PVS1 null-variant buckets per ClinGen SVI recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution p.D1018N
- variant does not meet PVS1 null-variant criteria
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders with a pathogenic variant observed in trans. No trans-phase data are available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame indels or stop-loss variants. This is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions without a known function. This is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact and low conservation. NM_016507.4:c.3052G>A is a missense variant (p.Asp1018Asn), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 limited to synonymous variants
Identifiers
- Gene
- CDK12
- Transcript
- NM_016507.4
- Coding (HGVS c.)
- NM_016507.4:c.3052G>A
- Protein (HGVS p.)
- NP_057591.2:p.(Asp1018Asn)
- GRCh38
- chr17:39520044 G>A
- GRCh37
- chr17:37676297 G>A
- COSMIC
- COSV109735027
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
39 / 1,613,882 alleles
AF 2.42e-05 · 0 homozygotes · FAF 5.8e-05
gnomAD v2.1
11 / 282,794 alleles
AF 3.89e-05 · 0 homozygotes · FAF 0.000106
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.4e-05 · 39 / 1,613,882 alleles · 0 hom · FAF 5.8e-05
| Middle Eastern2 / 6,080 | 0.00033 |
| East Asian6 / 44,890 | 0.00013 |
| Remaining individuals2 / 62,484 | 3.2e-05 |
| European (non-Finnish)27 / 1,179,986 | 2.3e-05 |
| Admixed American1 / 59,982 | 1.7e-05 |
| South Asian1 / 91,080 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.9e-05 · 11 / 282,794 alleles · 0 hom · FAF 0.00011
| East Asian5 / 19,952 | 0.00025 |
| European (non-Finnish)6 / 129,116 | 4.6e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.41653e-05; MAF= 0.00242%, 39/1613882 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328947; MAF= 0.03289%, 2/6080 alleles, homozygotes = 0); grpmax FAF= 5.802e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88976e-05; MAF= 0.00389%, 11/282794 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000250601; MAF= 0.02506%, 5/19952 alleles, homozygotes = 0); grpmax FAF= 0.00010624.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.240
- BayesDel
- -0.448
How the predictions were used
BP4 SupportingBP4 requires multiple lines of computational evidence suggesting no impact on the gene product. REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.448 (negative/benign prediction), and SpliceAI max delta 0.00 (no predicted splicing impact) collectively indicate no deleterious effect at the protein or splicing level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.24 (below 0.5 pathogenic threshold)
- BayesDel: -0.448 (negative
- benign prediction)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score 0.24 is below the typical pathogenic threshold (0.5), BayesDel score -0.448 is negative (benign prediction), and SpliceAI max delta score is 0.00 (no splice impact). No computational tool predicts a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.24 (below 0.5 pathogenic threshold)
- BayesDel: -0.448 (negative
- benign prediction)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact and low conservation. NM_016507.4:c.3052G>A is a missense variant (p.Asp1018Asn), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 limited to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.24. BayesDel score = -0.448466.
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
39 / 1,613,882 recorded alleles
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.3052G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37676297-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39520044-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39520044-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016507.4%3Ac.3052…
- OncoKB ↗www.oncokb.org/gene/CDK12/D1018N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=159084864
- 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= 2.41653e-05; MAF= 0.00242%, 39/1613882 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328947; MAF= 0.03289%, 2/6080 alleles, homozygotes = 0); grpmax FAF= 5.802e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88976e-05; MAF= 0.00389%, 11/282794 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000250601; MAF= 0.02506%, 5/19952 alleles, homozygotes = 0); grpmax FAF= 0.00010624.
gnomAD-Canada
Not available in 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 = 0.24. BayesDel score = -0.448466.
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; COSV109735027, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.