dbSNP rs186043011: CDK12:p.Gly1461Ser (chr17-39531224-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016507.4(CDK12):c.4381G>A(p.Gly1461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,364,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1461R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.384

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021136135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK12	NM_016507.4 link	c.4381G>A	p.Gly1461Ser	missense_variant	Exon 14 of 14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDK12	ENST00000447079.6 link	c.4381G>A	p.Gly1461Ser	missense_variant	Exon 14 of 14	1	NM_016507.4	ENSP00000398880.4
CDK12	ENST00000430627.6 link	c.4354G>A	p.Gly1452Ser	missense_variant	Exon 14 of 14	1		ENSP00000407720.2
CDK12	ENST00000584336.1 link	n.1343G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
CDK12	ENST00000559663.2 link	n.3760+4908G>A		intron_variant	Intron 13 of 20	5		ENSP00000453329.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000220

AC:

AN:

1364112

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

668332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30178

American (AMR)

AF:

0.00

AC:

AN:

28264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19844

East Asian (EAS)

AF:

0.00

AC:

AN:

38732

South Asian (SAS)

AF:

0.0000144

AC:

AN:

69386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5290

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1066550

Other (OTH)

AF:

0.00

AC:

AN:

56104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.4

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.046

.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.0082

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.38

PrimateAI

Benign

0.33

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.084

Sift

Benign

0.60

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.039

MutPred

0.13

.;Gain of phosphorylation at G1461 (P = 0.0269);

MVP

0.33

MPC

0.22

ClinPred

0.029

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over