13-26336975-G-A

Variant names:

• chr13-26336975-G-A
• rs17083838
• NM_001260.3:c.129-592G>A

Variant summary

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

The NM_001260.3(CDK8):​c.129-592G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0548 in 151,636 control chromosomes in the GnomAD database, including 258 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 (258 hom., cov: 31)
• Consequence: CDK8 NM_001260.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.856
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001260.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK8	NM_001260.3	MANE Select	c.129-592G>A		intron	N/A	NP_001251.1
	CDK8	NM_001318368.2		c.129-592G>A		intron	N/A	NP_001305297.1
	CDK8	NM_001346501.2		c.-333-592G>A		intron	N/A	NP_001333430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK8	ENST00000381527.8	TSL:1 MANE Select	c.129-592G>A		intron	N/A	ENSP00000370938.3
	CDK8	ENST00000536792.5	TSL:1	n.129-592G>A		intron	N/A	ENSP00000437696.1
	CDK8	ENST00000700501.1		n.129-12097G>A		intron	N/A	ENSP00000515024.1

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8299 AN: 151518 Hom.: 257 Cov.: 31

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0874

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0554

Gnomad OTH AF: 0.0668

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

GnomAD4 genome AF: 0.0548 AC: 8313 AN: 151636 Hom.: 258 Cov.: 31 AF XY: 0.0556 AC XY: 4124 AN XY: 74116

African (AFR) AF: 0.0412 AC: 1693 AN: 41086

American (AMR) AF: 0.0434 AC: 663 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3468

East Asian (EAS) AF: 0.0874 AC: 452 AN: 5170

South Asian (SAS) AF: 0.106 AC: 511 AN: 4806

European-Finnish (FIN) AF: 0.0704 AC: 742 AN: 10546

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0554 AC: 3764 AN: 67978

Other (OTH) AF: 0.0695 AC: 146 AN: 2102

Alfa AF: 0.0531 Hom.: 356

Bravo AF: 0.0506

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.24
DANN	Benign	0.60
PhyloP100		-0.86
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: rs17083838; hg19: chr13-26911112;