rs4770974

Positions:

• chr13-26375137-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CDK8	NM_001260.3	c.457-7677A>G		intron_variant		ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2	c.457-7677A>G		intron_variant			NP_001305297.1
CDK8	NM_001346501.2	c.-5-10074A>G		intron_variant			NP_001333430.1
CDK8	XM_047430033.1	c.277-7677A>G		intron_variant			XP_047285989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK8	ENST00000381527.8	c.457-7677A>G		intron_variant		1	NM_001260.3	ENSP00000370938	P1

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

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.217

Alfa AF: 0.240 Hom.: 1517

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

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

LitVar

Other links and lift over

dbSNP: rs4770974; hg19: chr13-26949274;