CCNH
protein-codingcyclin H, the group of Cyclins|CDK activating kinase complex
Gene summary
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery. A pseudogene of this gene is found on chromosome 4. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Nov 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~94.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CCNH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001239.4. 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 | 1 | 1 | 2 | |||
| missense | 47 | 3 | 50 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 52 | 1 | 3 | 56 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001230.1 | 9 | MANE Select | |
| Ensembl | ENSP00000256897.4 | 9 | MANE Select | |
| RefSeq | NP_001186118.1 | 8 | Standard | |
| RefSeq | NP_001350468.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Nucleotide excision repair - Homo sapiens (human)
- Cell cycle - Homo sapiens (human)
- Basal transcription factors - Homo sapiens (human)
- Cell Cycle
- Eukaryotic Transcription Initiation
Biological Process
- regulation of cyclin-dependent protein serine/threonine kinase activity
- transcription-coupled nucleotide-excision repair
- nucleotide-excision repair, preincision complex assembly
- regulation of transcription by RNA polymerase II
- transcription initiation from RNA polymerase I promoter
Molecular Function
- protein binding
- DNA-dependent ATPase activity
- RNA polymerase II CTD heptapeptide repeat kinase activity
- cyclin-dependent protein serine/threonine kinase regulator activity
Cellular Component
- nucleus
- nucleoplasm
- transcription factor TFIIH holo complex
- cyclin-dependent protein kinase activating kinase holoenzyme complex
- transcription factor TFIIK complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000256897
- Coding exons
- 9
- Length
- 21526
- Individuals with no LoFs
- 125679
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125744
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.102 | 168 | 172 | 0.978 | 0.00000869 | 2123 |
| Missense (PolyPhen) | 36 | 37.336 | 0.96423 | 468 | ||
| Synonymous | -0.427 | 68 | 63.7 | 1.07 | 0.00000344 | 582 |
| Loss of Function | 2.16 | 8 | 17.8 | 0.448 | 9.30e-7 | 236 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0014 | 0.0014 | notable |
| Latino/Admixed American | 0.000092 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00027 | 0.00026 | rare |
| South Asian | 0.00021 | 0.00020 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulates CDK7, the catalytic subunit of the CDK- activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II. Its expression and activity are constant throughout the cell cycle. {ECO:0000269|PubMed:10024882, ECO:0000269|PubMed:7533895}.;
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- LoFtool
- 0.848
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.73
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |