CDK8

Chr 13AD

cyclin dependent kinase 8

Also known as: IDDHBA, K35

NCBI Gene: 1024 ENSG00000132964 UniProt: P49336 OMIM: 603184

This gene encodes a cyclin-dependent kinase that is a component of the Mediator complex, which regulates transcription by serving as a bridge between gene-specific regulatory proteins and RNA polymerase II transcription machinery. Mutations cause intellectual developmental disorder with hypotonia and behavioral abnormalities with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.418), indicating that such variants are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

ADLOEUF 0.421 OMIM phenotype

Clinical Summary— CDK8

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 67 VUS of 117 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.42LOEUF

pLI 0.410

Z-score 4.04

OE 0.22 (0.13–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.68Z-score

OE missense 0.35 (0.29–0.41)

87 obs / 251.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.42)

0≤0.351.4

Missense OE?0.35 (0.29–0.41)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 7 / 31.4Missense obs/exp: 87 / 251.2Syn Z: 0.59

ClinVar Variant Classifications

117 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic10

VUS67

Likely Benign10

Benign2

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	9	0	0	10
Likely Pathogenic	0	10	0	0	10
VUS	3	62	2	0	67
Likely Benign	0	3	1	6	10
Benign	0	0	2	0	2
Conflicting	—				1
Total	4	84	5	6	100

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

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33 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap CDK8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →