13-26254726-C-G

Position:

• chr13-26254726-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_001260.3(CDK8):​c.85C>G​(p.Arg29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDK8 NM_001260.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.59

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a binding_site (size 8) in uniprot entity CDK8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001260.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 13-26254726-C-G is Pathogenic according to our data. Variant chr13-26254726-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 805982.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK8	NM_001260.3	c.85C>G	p.Arg29Gly	missense_variant	1/13	ENST00000381527.8
CDK8	NM_001318368.2	c.85C>G	p.Arg29Gly	missense_variant	1/13
CDK8	NM_001346501.2	c.-377C>G		5_prime_UTR_variant	1/12
CDK8	XM_047430033.1	c.-146C>G		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK8	ENST00000381527.8	c.85C>G	p.Arg29Gly	missense_variant	1/13	1	NM_001260.3	P1
CDK8	ENST00000536792.5	c.85C>G	p.Arg29Gly	missense_variant, NMD_transcript_variant	1/12	1
CDK8	ENST00000700501.1	c.85C>G	p.Arg29Gly	missense_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual developmental disorder with hypotonia and behavioral abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.40
Sift	Benign	0.046	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.70		Loss of MoRF binding (P = 0.0114);
MVP		0.64
MPC		2.1
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.58
gMVP		0.90

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: rs1593218885; hg19: chr13-26828863;