rs61747430

chr17-39525947-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016507.4(CDK12):c.3391A>G(p.Ile1131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,184 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (18 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.07

Genes affected

CDK12 (HGNC:24224): (cyclin dependent kinase 12) Enables RNA polymerase II CTD heptapeptide repeat kinase activity and cyclin binding activity. Involved in phosphorylation of RNA polymerase II C-terminal domain; protein autophosphorylation; and regulation of MAP kinase activity. Located in nuclear speck. Part of cyclin K-CDK12 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022045374).
• BP6: Variant 17-39525947-A-G is Benign according to our data. Variant chr17-39525947-A-G is described in ClinVar as [Benign]. Clinvar id is 133857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1344/152296) while in subpopulation AFR AF= 0.0306 (1273/41560). AF 95% confidence interval is 0.0292. There are 19 homozygotes in gnomad4. There are 628 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4	c.3391A>G	p.Ile1131Val	missense_variant	13/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6	c.3391A>G	p.Ile1131Val	missense_variant	13/14	1	NM_016507.4	P4
CDK12	ENST00000430627.6	c.3391A>G	p.Ile1131Val	missense_variant	13/14	1		A1
CDK12	ENST00000584632.5	c.3388A>G	p.Ile1130Val	missense_variant	13/13	5
CDK12	ENST00000559663.2	c.3391A>G	p.Ile1131Val	missense_variant, NMD_transcript_variant	13/21	5

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1344 AN: 152178 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00241 AC: 605 AN: 251406 Hom.: 10 AF XY: 0.00167 AC XY: 227 AN XY: 135870

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000866 AC: 1266 AN: 1461888 Hom.: 18 Cov.: 32 AF XY: 0.000708 AC XY: 515 AN XY: 727244

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00882 AC: 1344 AN: 152296 Hom.: 19 Cov.: 32 AF XY: 0.00843 AC XY: 628 AN XY: 74472

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00394 Hom.: 3

Bravo AF: 0.0107

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CDK12-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	16
Dann	Benign	0.73
DEOGEN2	Benign	0.0083	T;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.81	N;N
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.10, 0.12
MVP		0.25
MPC		0.16
ClinPred		0.0043	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61747430; hg19: chr17-37682200; COSMIC: COSV104713587; COSMIC: COSV104713587;