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.1 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.2 The variant is absent from ClinVar and no publications mention this specific variant, limiting clinical interpretation to population and computational data.3 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).4
CDK12
Final classification
VUS
CDK12 c.3052G>A · p.Asp1018Asn
CDK12
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.
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.
Classification rationale
PM2
BP4
VUS
CDK12 c.3052G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_016507.4 · variants mapped to exon structure
CDK12
NM_016507.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: AF=0.00389% (11/282794)hom=0
✓
BP4
supporting
Benign
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.
REVEL: 0.24 (below 0.5 pathogenic threshold)BayesDel: -0.448 (negativebenign prediction)
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change resulting in the same amino acid substitution (D1018N) with a known pathogenic classification.
PS2
PS2 requires a de novo observation (maternity and paternity confirmed).
PS3
PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect.
PS4
PS4 requires a significantly increased prevalence of the variant in affected individuals compared to controls.
PM1
PM1 requires the variant to be located in a mutational hotspot or critical well-established functional domain.
PM5
PM5 requires a different pathogenic missense variant at the same codon (Asp1018).
PM6
PM6 requires a de novo observation without confirmed maternity and paternity.
PP1
PP1 requires cosegregation of the variant with disease in multiple affected family members.
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.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect.
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.
PP5
PP5 requires the variant to be classified as pathogenic by a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory).
Benign
BA1
BA1 requires an allele frequency >1% in a general population.
BS1
BS1 requires an allele frequency >0.3% in a general population.
BS2
BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age.
BS3
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.
BS4
BS4 requires lack of segregation of the variant with disease in affected family members.
BP1
BP1 requires a missense variant in a gene where only truncating variants are the primary known disease mechanism.
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.
BP5
BP5 requires an alternative molecular basis for disease to have been identified in the affected individual.
BP6
BP6 requires the variant to be classified as benign by a reputable source (e.g., ClinVar expert panel).
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0024%
· 39 / 1,613,882
0 hom · FAF 0.0058%
0 hom · FAF 0.0058%
Middle Eastern 2 / 6,080 |
0.033% |
East Asian 6 / 44,890 |
0.013% |
Remaining individuals 2 / 62,484 |
0.0032% |
European (non-Finnish) 27 / 1,179,986 |
0.0023% |
Admixed American 1 / 59,982 |
0.0017% |
South Asian 1 / 91,080 |
0.0011% |
+ 4 not observed (European (Finnish), Amish, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0039%
· 11 / 282,794
0 hom · FAF 0.011%
0 hom · FAF 0.011%
East Asian 5 / 19,952 |
0.025% |
European (non-Finnish) 6 / 129,116 |
0.0046% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109735027, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links