CDK8
protein-codingcyclin dependent kinase 8, the group of Cyclin dependent kinases|Mediator complex
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~166.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032897
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032897
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0032897
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular
Rationale: Individuals have been described as affected with a range of cardiovascular anomalies, including potentially occult anomalies requiring interventions, and awareness may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CDK8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001260.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 8 | 8 | ||||
| missense | 9 | 11 | 78 | 4 | 102 | |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 10 | 11 | 84 | 12 | 0 | 117 |
Highest pathogenic variant AF is 0.000003103306
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001251.1 | 13 | MANE Select | |
| Ensembl | ENSP00000370938.3 | 13 | MANE Select | |
| RefSeq | NP_001305297.1 | 13 | Standard | |
| RefSeq | NP_001333430.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Sterol Regulatory Element-Binding Proteins (SREBP) signalling
- H19 action Rb-E2F1 signaling and CDK-β-catenin activity
- Developmental Biology
- Disease
- Signal Transduction
Biological Process
- transcription initiation from RNA polymerase II promoter
- protein phosphorylation
- positive regulation of transcription by RNA polymerase II
- regulation of cell cycle
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- cyclin-dependent protein serine/threonine kinase activity
- protein binding
- ATP binding
Cellular Component
- nucleus
- nucleoplasm
- nucleolus
- mediator complex
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000381527
- Coding exons
- 13
- Length
- 151100
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.68 | 87 | 251 | 0.346 | 0.0000125 | 3048 |
| Missense (PolyPhen) | 11 | 64.52 | 0.17049 | 769 | ||
| Synonymous | 0.590 | 79 | 86.0 | 0.919 | 0.00000433 | 833 |
| Loss of Function | 4.04 | 7 | 31.4 | 0.223 | 0.00000182 | 354 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000036 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. {ECO:0000269|PubMed:10993082, ECO:0000269|PubMed:15546612}.;
Recessive Scores
- pRec
- 0.203
Intolerance Scores
- LoFtool
- 0.425
- RVIS EVS
- -0.25
- RVIS percentile EVS
- 35.42
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |