rs61747430

Positions:

chr17-39525947-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000447079.6(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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 18 hom. )

Consequence

CDK12
ENST00000447079.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 1.07

Variant links:

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]

CDK12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 [Likely_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. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK12	NM_016507.4 linkuse as main transcript	c.3391A>G	p.Ile1131Val	missense_variant	13/14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6 linkuse as main transcript	c.3391A>G	p.Ile1131Val	missense_variant	13/14	1	NM_016507.4	ENSP00000398880	P4	Q9NYV4-1
CDK12	ENST00000430627.6 linkuse as main transcript	c.3391A>G	p.Ile1131Val	missense_variant	13/14	1		ENSP00000407720	A1	Q9NYV4-2
CDK12	ENST00000584632.5 linkuse as main transcript	c.3388A>G	p.Ile1130Val	missense_variant	13/13	5		ENSP00000464641
CDK12	ENST00000559663.2 linkuse as main transcript	c.3391A>G	p.Ile1131Val	missense_variant, NMD_transcript_variant	13/21	5		ENSP00000453329

Frequencies

GnomAD3 genomes

AF:

0.00883

AC:

1344

AN:

152178

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00167

AC XY:

227

AN XY:

135870

show subpopulations

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.:

Cov.:

AF XY:

0.000708

AC XY:

515

AN XY:

727244

show subpopulations

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.:

Cov.:

AF XY:

0.00843

AC XY:

628

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.0107

ESP6500AA

AF:

0.0336

AC:

148

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00294

AC:

357

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CDK12-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.0083

T;.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.16

.;N;N

MutationTaster

Benign

0.81

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.010

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.21

.;T;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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over