dbSNP rs587778180: CDK12:p.Tyr1468His (chr17-39531245-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016507.4(CDK12):c.4402T>C(p.Tyr1468His) variant causes a missense change. The variant allele was found at a frequency of 0.0000086 in 1,512,160 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1468C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000074 ( 0 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 4.53

Publications

1 publications found

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 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17783532).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016507.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK12	NM_016507.4	MANE Select	c.4402T>C	p.Tyr1468His	missense	Exon 14 of 14	NP_057591.2
	CDK12	NM_015083.4		c.4375T>C	p.Tyr1459His	missense	Exon 14 of 14	NP_055898.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDK12	ENST00000447079.6	TSL:1 MANE Select	c.4402T>C	p.Tyr1468His	missense	Exon 14 of 14	ENSP00000398880.4
CDK12	ENST00000430627.6	TSL:1	c.4375T>C	p.Tyr1459His	missense	Exon 14 of 14	ENSP00000407720.2
CDK12	ENST00000922307.1		c.4324T>C	p.Tyr1442His	missense	Exon 13 of 13	ENSP00000592366.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152026

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:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000292

AC:

AN:

171000

AF XY:

0.0000330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000735

AC:

AN:

1360134

Hom.:

Cov.:

AF XY:

0.0000105

AC XY:

AN XY:

666326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30116

American (AMR)

AF:

0.00

AC:

AN:

27566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19776

East Asian (EAS)

AF:

0.000156

AC:

AN:

38508

South Asian (SAS)

AF:

0.00

AC:

AN:

68382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065054

Other (OTH)

AF:

0.0000716

AC:

AN:

55850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000169

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Benign

0.063

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.37

PhyloP100

4.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.018

Polyphen

0.76

Vest4

0.42

MutPred

0.31

Loss of phosphorylation at Y1468 (P = 0.0206)

MVP

0.60

MPC

0.58

ClinPred

0.84

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.34

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over