rs34070318

Positions:

chr17-39530667-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.3824C>T(p.Pro1275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,612,074 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.016 ( 253 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.35

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=0.006244242).

BP6

Variant 17-39530667-C-T is Benign according to our data. Variant chr17-39530667-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0108 (1644/152096) while in subpopulation NFE AF= 0.0163 (1107/67994). AF 95% confidence interval is 0.0155. There are 14 homozygotes in gnomad4. There are 781 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1644 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK12	NM_016507.4 linkuse as main transcript	c.3824C>T	p.Pro1275Leu	missense_variant	14/14	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.3824C>T	p.Pro1275Leu	missense_variant	14/14	1	NM_016507.4	ENSP00000398880	P4	Q9NYV4-1
CDK12	ENST00000430627.6 linkuse as main transcript	c.3797C>T	p.Pro1266Leu	missense_variant	14/14	1		ENSP00000407720	A1	Q9NYV4-2
CDK12	ENST00000584336.1 linkuse as main transcript	n.786C>T		non_coding_transcript_exon_variant	1/1
CDK12	ENST00000559663.2 linkuse as main transcript	c.3760+4351C>T		intron_variant, NMD_transcript_variant		5		ENSP00000453329

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1644

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00305

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00617

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0116

GnomAD3 exomes

AF:

0.0116

AC:

2886

AN:

248522

Hom.:

AF XY:

0.0120

AC XY:

1618

AN XY:

134684

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.0237

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00407

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0158

AC:

23008

AN:

1459978

Hom.:

253

Cov.:

AF XY:

0.0153

AC XY:

11144

AN XY:

726124

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00414

Gnomad4 ASJ exome

AF:

0.0238

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00495

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.0179

Gnomad4 OTH exome

AF:

0.0148

GnomAD4 genome

AF:

0.0108

AC:

1644

AN:

152096

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

781

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00304

Gnomad4 AMR

AF:

0.00616

Gnomad4 ASJ

AF:

0.0228

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.0184

Gnomad4 NFE

AF:

0.0163

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0150

Hom.:

Bravo

AF:

0.00983

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.0166

AC:

143

ExAC

AF:

0.0116

AC:

1409

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0168

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

Jun 10, 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

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0062

T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.5

.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.7

D;N

REVEL

Benign

0.26

Sift

Benign

0.14

T;T

Sift4G

Uncertain

0.0060

D;T

Polyphen

1.0

D;D

Vest4

0.34

MPC

0.20

ClinPred

0.022

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.25

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