rs34070318

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. P1275P) has been classified 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

Publications

19 publications found

Variant links:

COSMIC-nc: COSV71002230

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 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

CDK12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK12	NM_016507.4 link	c.3824C>T	p.Pro1275Leu	missense_variant	Exon 14 of 14	ENST00000447079.6	NP_057591.2	Q9NYV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDK12	ENST00000447079.6 link	c.3824C>T	p.Pro1275Leu	missense_variant	Exon 14 of 14	1	NM_016507.4	ENSP00000398880.4	Q9NYV4-1
CDK12	ENST00000430627.6 link	c.3797C>T	p.Pro1266Leu	missense_variant	Exon 14 of 14	1		ENSP00000407720.2	Q9NYV4-2
CDK12	ENST00000584336.1 link	n.786C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
CDK12	ENST00000559663.2 link	n.3760+4351C>T		intron_variant	Intron 13 of 20	5		ENSP00000453329.2	H0YLT2

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

GnomAD2 exomes

AF:

0.0116

AC:

2886

AN:

248522

AF XY:

0.0120

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 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

African (AFR)

AF:

0.00212

AC:

AN:

33450

American (AMR)

AF:

0.00414

AC:

185

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

621

AN:

26044

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00495

AC:

426

AN:

86140

European-Finnish (FIN)

AF:

0.0166

AC:

885

AN:

53298

Middle Eastern (MID)

AF:

0.00522

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0179

AC:

19893

AN:

1110664

Other (OTH)

AF:

0.0148

AC:

895

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

1235

2470

3706

4941

6176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

762

1524

2286

3048

3810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0108

AC:

1644

AN:

152096

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

781

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00304

AC:

126

AN:

41482

American (AMR)

AF:

0.00616

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00353

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0184

AC:

195

AN:

10600

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0163

AC:

1107

AN:

67994

Other (OTH)

AF:

0.0114

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0137

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

Jun 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

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

(source)

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

PhyloP100

2.4

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

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over