Genetic Variant NM_001260.3:c.457-7375A>T (chr13-26375439-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001260.3(CDK8):c.457-7375A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 152,254 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.057 ( 410 hom., cov: 33)

Consequence

CDK8
NM_001260.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.347

Publications

1 publications found

Variant links:

Genes affected

CDK8 (HGNC:1779): (cyclin dependent kinase 8) This gene encodes a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit, cyclin C, are components of the Mediator transcriptional regulatory complex, involved in both transcriptional activation and repression by phosphorylation of the carboxy-terminal domain of the largest subunit of RNA polymerase II. This kinase regulates transcription by targeting the cyclin-dependent kinase 7 subunits of the general transcription initiation factor IIH, thus providing a link between the Mediator complex and the basal transcription machinery. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

CDK8 Gene-Disease associations (from GenCC):

intellectual developmental disorder with hypotonia and behavioral abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

CDK8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CDK8	NM_001260.3 link	c.457-7375A>T	intron_variant	Intron 4 of 12	ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2 link	c.457-7375A>T	intron_variant	Intron 4 of 12		NP_001305297.1
CDK8	NM_001346501.2 link	c.-5-9772A>T	intron_variant	Intron 4 of 11		NP_001333430.1
CDK8	XM_047430033.1 link	c.277-7375A>T	intron_variant	Intron 5 of 13		XP_047285989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK8	ENST00000381527.8 link	c.457-7375A>T		intron_variant	Intron 4 of 12	1	NM_001260.3	ENSP00000370938.3

Frequencies

GnomAD3 genomes

AF:

0.0568

AC:

8643

AN:

152136

Hom.:

409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0811

Gnomad ASJ

AF:

0.0654

Gnomad EAS

AF:

0.0628

Gnomad SAS

AF:

0.0930

Gnomad FIN

AF:

0.00952

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0202

Gnomad OTH

AF:

0.0590

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0569

AC:

8657

AN:

152254

Hom.:

410

Cov.:

AF XY:

0.0589

AC XY:

4383

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.115

AC:

4795

AN:

41538

American (AMR)

AF:

0.0809

AC:

1237

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0654

AC:

227

AN:

3472

East Asian (EAS)

AF:

0.0628

AC:

325

AN:

5178

South Asian (SAS)

AF:

0.0931

AC:

448

AN:

4814

European-Finnish (FIN)

AF:

0.00952

AC:

101

AN:

10612

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0202

AC:

1376

AN:

68030

Other (OTH)

AF:

0.0621

AC:

131

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

402

804

1207

1609

2011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0390

Hom.:

Bravo

AF:

0.0625

Asia WGS

AF:

0.109

AC:

379

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

2.9

(source)

DANN

Benign

0.30

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over