13-26340591-C-T

Variant names:

• chr13-26340591-C-T
• rs2420130
• NM_001260.3:c.204+2949C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001260.3(CDK8):​c.204+2949C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 152,166 control chromosomes in the GnomAD database, including 365 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 0.055 (365 hom., cov: 32)
• Consequence: CDK8 NM_001260.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106
• Publications: 4 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK8	NM_001260.3	c.204+2949C>T		intron_variant	Intron 2 of 12	ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2	c.204+2949C>T		intron_variant	Intron 2 of 12		NP_001305297.1
CDK8	NM_001346501.2	c.-258+2949C>T		intron_variant	Intron 2 of 11		NP_001333430.1
CDK8	XM_047430033.1	c.24+2949C>T		intron_variant	Intron 3 of 13		XP_047285989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK8	ENST00000381527.8	c.204+2949C>T		intron_variant	Intron 2 of 12	1	NM_001260.3	ENSP00000370938.3

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8372 AN: 152050 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.0628

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.00991

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0570

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

GnomAD4 genome AF: 0.0551 AC: 8383 AN: 152166 Hom.: 365 Cov.: 32 AF XY: 0.0573 AC XY: 4262 AN XY: 74386

African (AFR) AF: 0.108 AC: 4502 AN: 41498

American (AMR) AF: 0.0800 AC: 1222 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.0627 AC: 325 AN: 5180

South Asian (SAS) AF: 0.0929 AC: 447 AN: 4814

European-Finnish (FIN) AF: 0.00991 AC: 105 AN: 10600

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0207 AC: 1411 AN: 68014

Other (OTH) AF: 0.0602 AC: 127 AN: 2108

Alfa AF: 0.0532 Hom.: 137

Bravo AF: 0.0604

Asia WGS AF: 0.109 AC: 378 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.80
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2420130; hg19: chr13-26914728;