rs61741615

Positions:

chr17-39526140-C-T

Variant summary

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

The NM_016507.4(CDK12):c.3584C>T(p.Thr1195Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,614,192 control chromosomes in the GnomAD database, including 41 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 0.0093 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 22 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.790

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=0.002410978).

BP6

Variant 17-39526140-C-T is Benign according to our data. Variant chr17-39526140-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133859.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 = 0.00928 (1413/152302) while in subpopulation AFR AF= 0.0321 (1332/41552). AF 95% confidence interval is 0.0306. There are 19 homozygotes in gnomad4. There are 697 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK12	NM_016507.4 linkuse as main transcript	c.3584C>T	p.Thr1195Met	missense_variant	13/14	ENST00000447079.6	NP_057591.2	Q9NYV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDK12	ENST00000447079.6 linkuse as main transcript	c.3584C>T	p.Thr1195Met	missense_variant	13/14	1	NM_016507.4	ENSP00000398880.4	Q9NYV4-1
CDK12	ENST00000430627.6 linkuse as main transcript	c.3584C>T	p.Thr1195Met	missense_variant	13/14	1		ENSP00000407720.2	Q9NYV4-2
CDK12	ENST00000584632.5 linkuse as main transcript	c.3581C>T	p.Thr1194Met	missense_variant	13/13	5		ENSP00000464641.1	J3QSD7
CDK12	ENST00000559663.2 linkuse as main transcript	n.3584C>T		non_coding_transcript_exon_variant	13/21	5		ENSP00000453329.2	H0YLT2

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1388

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00230

AC:

578

AN:

251316

Hom.:

AF XY:

0.00169

AC XY:

229

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0322

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000910

AC:

1330

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000789

AC XY:

574

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0321

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00928

AC:

1413

AN:

152302

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

697

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0321

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0329

AC:

145

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00273

AC:

332

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: 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

Apr 04, 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

Likely 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

0.081

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

T;.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

.;L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.080

Sift

Uncertain

0.011

.;D;D

Sift4G

Uncertain

0.039

D;T;T

Polyphen

0.0040, 0.0020

.;B;B

Vest4

0.14, 0.14

MVP

0.41

MPC

0.51

ClinPred

0.017

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.24

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