Variant 17-39462082-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016507.4(CDK12):c.11C>T(p.Ser4Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23529139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4 linkuse as main transcript	c.11C>T	p.Ser4Leu	missense_variant	1/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6 linkuse as main transcript	c.11C>T	p.Ser4Leu	missense_variant	1/14	1	NM_016507.4	P4	Q9NYV4-1
CDK12	ENST00000430627.6 linkuse as main transcript	c.11C>T	p.Ser4Leu	missense_variant	1/14	1		A1	Q9NYV4-2
CDK12	ENST00000584632.5 linkuse as main transcript	c.11C>T	p.Ser4Leu	missense_variant	1/13	5
CDK12	ENST00000559663.2 linkuse as main transcript	c.11C>T	p.Ser4Leu	missense_variant, NMD_transcript_variant	1/21	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251032

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461434

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.11C>T (p.S4L) alteration is located in exon 1 (coding exon 1) of the CDK12 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.020

T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.86

D;D;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Uncertain

-0.21

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.56

Sift4G

Benign

0.10

T;T;T

Polyphen

0.99, 0.98

.;D;D

Vest4

0.14, 0.19

MutPred

0.15

Loss of phosphorylation at S4 (P = 0.0065);Loss of phosphorylation at S4 (P = 0.0065);Loss of phosphorylation at S4 (P = 0.0065);

MVP

0.48

MPC

0.30

ClinPred

0.76

GERP RS

4.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.26

gMVP

0.042

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