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.1 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.2 No functional studies, de novo observations, segregation data, case-control data, or ClinVar classifications were available to support additional pathogenic or benign criteria.3 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).4
CDK12
Final classification
VUS
PM2BP4
CDK12
c.2351G>A
p.Arg784Gln
This variant
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.
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.
Classification rationale
PM2
BP4
VUS
CDK12 c.2351G>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 · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: 3/275404 alleles (AF 0.00109%)gnomAD v4.1: 18/1
✓
BP4
supporting
Benign
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).
REVEL 0.075 (strongly benign)BayesDel −0.517 (benign)SpliceAI max delta 0.01 (no splice impact)
Assessed · not applied
· 10 not met · 8 not assessed
Pathogenic
PS1
No previously established pathogenic variant with the same amino acid change (p.Arg784Gln) has been reported.
PS2
No de novo data available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrate a damaging effect.
PS4
No case-control or prevalence data comparing affected vs.
PM1
Residue 784 does not lie within a statistically significant mutational hotspot, and the variant is not listed in the Cancer Hotspots database.
PM6
No de novo data available for this variant.
PP1
No cosegregation data available for this variant.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease.
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).
PP4
No patient phenotype information was provided for this case.
Benign
BA1
The maximum population allele frequency (0.028% in gnomAD v2.1 Remaining individuals) is far below the 1% threshold for BA1.
BS1
The maximum population allele frequency (0.028% in gnomAD v2.1 Remaining individuals) is below the 0.3% threshold for BS1.
BS2
No homozygous individuals have been observed in gnomAD v2.1, v4.1, or gnomAD-Canada.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect.
BS4
No segregation data available to assess lack of cosegregation with disease.
BP1
BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease.
BP2
No data available regarding observation in trans with a pathogenic variant.
BP5
No data available regarding an alternate molecular basis for disease in a case harboring this variant.
N/A · 6
PVS1 · PM5 · PP5 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0011%
· 18 / 1,609,482
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
European (Finnish) 10 / 63,854 |
0.016% |
Remaining individuals 1 / 62,320 |
0.0016% |
European (non-Finnish) 7 / 1,177,366 |
0.00059% |
+ 7 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0011%
· 3 / 275,404
0 hom
0 hom
Remaining individuals 2 / 7,106 |
0.028% |
European (non-Finnish) 1 / 124,794 |
0.0008% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), 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 = 0.01). REVEL score = 0.075. BayesDel score = -0.516897.
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; COSV104713462, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links