rs4770974

Variant names:

• chr13-26375137-A-G
• rs4770974
• NM_001260.3:c.457-7677A>G

Variant summary

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

The NM_001260.3(CDK8):​c.457-7677A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,152 control chromosomes in the GnomAD database, including 4,272 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 0.21 (4272 hom., cov: 32)
• Consequence: CDK8 NM_001260.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK8	NM_001260.3	c.457-7677A>G		intron_variant	Intron 4 of 12	ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2	c.457-7677A>G		intron_variant	Intron 4 of 12		NP_001305297.1
CDK8	NM_001346501.2	c.-5-10074A>G		intron_variant	Intron 4 of 11		NP_001333430.1
CDK8	XM_047430033.1	c.277-7677A>G		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	c.457-7677A>G		intron_variant	Intron 4 of 12	1	NM_001260.3	ENSP00000370938.3

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32343 AN: 152034 Hom.: 4278 Cov.: 32

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.219

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

GnomAD4 genome AF: 0.212 AC: 32319 AN: 152152 Hom.: 4272 Cov.: 32 AF XY: 0.221 AC XY: 16424 AN XY: 74384

African (AFR) AF: 0.0504 AC: 2095 AN: 41558

American (AMR) AF: 0.260 AC: 3976 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 854 AN: 3466

East Asian (EAS) AF: 0.367 AC: 1900 AN: 5176

South Asian (SAS) AF: 0.258 AC: 1243 AN: 4818

European-Finnish (FIN) AF: 0.331 AC: 3492 AN: 10548

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18128 AN: 67974

Other (OTH) AF: 0.217 AC: 458 AN: 2112

Alfa AF: 0.241 Hom.: 1891

Bravo AF: 0.197

Asia WGS AF: 0.283 AC: 982 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.69
PhyloP100		1.8
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: rs4770974; hg19: chr13-26949274;