NM_001260.3:c.100C>T

Variant names:

• chr13-26254741-C-T
• NM_001260.3:c.100C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001260.3(CDK8):​c.100C>T​(p.His34Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H34D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDK8 NM_001260.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 8) in uniprot entity CDK8_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001260.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK8	NM_001260.3	c.100C>T	p.His34Tyr	missense_variant	Exon 1 of 13	ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2	c.100C>T	p.His34Tyr	missense_variant	Exon 1 of 13		NP_001305297.1
CDK8	NM_001346501.2	c.-362C>T		5_prime_UTR_variant	Exon 1 of 12		NP_001333430.1
CDK8	XM_047430033.1	c.-131C>T		5_prime_UTR_variant	Exon 1 of 14		XP_047285989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK8	ENST00000381527.8	c.100C>T	p.His34Tyr	missense_variant	Exon 1 of 13	1	NM_001260.3	ENSP00000370938.3
CDK8	ENST00000536792.5	n.100C>T		non_coding_transcript_exon_variant	Exon 1 of 12	1		ENSP00000437696.1
CDK8	ENST00000700501.1	n.100C>T		non_coding_transcript_exon_variant	Exon 1 of 12			ENSP00000515024.1
CDK8	ENST00000700502.1	n.-249C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 31, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.12	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.37
Sift	Benign	0.10	T
Sift4G	Benign	0.57	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.54		Gain of methylation at K39 (P = 0.0667);
MVP		0.53
MPC		2.4
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-26828878;