CCNO
protein-codingcyclin O, the group of Cyclins
Gene summary
This gene encodes a member of the cyclin protein family, and the encoded protein is involved in regulation of the cell cycle. Disruption of this gene is associated with primary ciliary dyskinesia-19. Alternative splicing results in multiple transcript variants. This gene, which has a previous symbol of UNG2, was erroneously identified as a uracil DNA glycosylase in PubMed ID: 2001396. A later publication, PubMed ID: 8419333, identified this gene's product as a cyclin protein family member. The UNG2 symbol is also used as a specific protein isoform name for the UNG gene (GeneID 7374), so confusion exists in the scientific literature and in some databases for these two genes. [provided by RefSeq, Jul 2014]
- CCNU
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014378
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016575
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014378
Submitter: ClinGen
The *CCNO* gene was first reported in relation to primary ciliary dyskinesia in 2014 (Wallmeier et al., PMID: 24747639). The specific disease entity, Primary Ciliary Dyskinesia 29, is one of at least 50 different primary ciliary dyskinesias distinguished by a specific monogenetic cause. Affected patients frequently present as neonates or in early childhood with recurrent respiratory infections including sinusitis, as well as decreased nasal nitric oxide, otitis media, and/or bronchiectasis. The reported cases presented with a severe clinical phenotype, including severe lung disease, and rarely hydrocephalus and ventriculomegaly. Laterality defects were not observed for any of the reported patients. Biopsies of upper and bronchial respiratory epithelial cells showed a complete absence or markedly reduced numbers of cilia, and in vitro ciliogenesis culture experiments demonstrated a severe defect in multiple motile cilia (MMC) generation, associated with insufficient centriole numbers and decreased basal bodies. Ciliary ultrastructure in the few expressed cilia was normal but beating was uncoordinated (PMID: 24747639, PMID: 24824133, PMID: 34102041). Due to this, Primary Ciliary Dyskinesia caused by pathogenic variants in *CCNO* belong to a group of disorders known as “reduced generation of multiple motile cilia” or RGMMC, associated with hydrocephalus in humans. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and mode of inheritance (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited *CCNO* variants have been lumped into a single disease entity, referred to as Primary Ciliary Dyskinesia 29 (MONDO:0014378, OMIM #615872). Nine suspected pathogenic variants were scored as part of this curation (six frameshift, one nonsense and two missense), which have been collectively reported in fifteen probands (as well as affected family members) in four publications (PMID: 24747639, PMID: 24824133, PMID: 34102041, PMID: 26777464). More case-level evidence is available in the literature (PMID: 26139845) but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence (12 points). This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by the absence of a gene product (PMID: 24747639). All probands scored in this curation harbored two variant alleles within the *CCNO* locus. This gene-disease association is also supported by experimental evidence that human tissues exhibiting the highest levels of *CCNO* expression include tissue types relevant to disease and known to have motile cilia, including the lung, fallopian tube, brain, and testis (PMID: 23715323). More experimental evidence includes that *CCNO* normally localizes to the apical cytoplasm and is an essential component for generation of MMC, functional alterations in patient cells consistent with a critical role in MMC generation, and mislocalization in the cytoplasm and altered expression in PCD patient tissue. Model organisms (mouse and frog) show reduced numbers of MMC and characteristic phenotypes of MMC dysfunction, similar to those observed in patients (PMID: 25712475, PMID: 24747639, PIMD: 29245899). In summary, *CCNO* is definitively associated with autosomal recessive primary ciliary dyskinesia 29. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 19, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014378
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014378
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Genitourinary; Pulmonary
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Pulmonary
Rationale: Pulmonary and audiologic surveillance may be beneficial to assess respiratory and hearing function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial, though measures including lobectomy or lung transplantation may be necessary
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CCNO variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021147.5. 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 | 72 | 72 | ||||
| missense | 1 | 3 | 112 | 10 | 2 | 128 |
| nonsense | 4 | 4 | 8 | |||
| start loss | 0 | |||||
| frameshift | 23 | 10 | 33 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 4 | |||
| Total | 28 | 19 | 114 | 82 | 2 | 245 |
Highest pathogenic variant AF is 0.00011009793
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_066970.3 | 3 | MANE Select | |
| Ensembl | ENSP00000282572.4 | 3 | MANE Select | |
| Ensembl | ENSP00000422485.1 | 1 | Standard | |
| Ensembl | ENSP00000794625.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of cyclin-dependent protein serine/threonine kinase activity
- mitotic cell cycle
- protein phosphorylation
- regulation of mitotic nuclear division
- positive regulation of cell population proliferation
Molecular Function
- protein kinase activity
- cyclin-dependent protein serine/threonine kinase regulator activity
- protein kinase binding
Cellular Component
- cyclin-dependent protein kinase holoenzyme complex
- nucleus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000282572
- Coding exons
- 3
- Length
- 2529
- Individuals with no LoFs
- 125648
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 55
- Defined
- 125703
- p
- 0.000219
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.136 | 198 | 193 | 1.03 | 0.00000869 | 2183 |
| Missense (PolyPhen) | 63 | 67.128 | 0.93851 | 816 | ||
| Synonymous | -0.431 | 99 | 93.7 | 1.06 | 0.00000447 | 775 |
| Loss of Function | 1.22 | 5 | 8.94 | 0.559 | 3.82e-7 | 100 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000086 | 0.000062 | rare |
| Latino/Admixed American | 0.00013 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00076 | 0.00065 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00026 | 0.00022 | rare |
| South Asian | 0.00036 | 0.00033 | rare |
| Other | 0.00053 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Specifically required for generation of multiciliated cells, possibly by promoting a cell cycle state compatible with centriole amplification and maturation. Acts downstream of MCIDAS to promote mother centriole amplification and maturation in preparation for apical docking. {ECO:0000269|PubMed:24747639, ECO:0000269|PubMed:26777464}.;
- Disease
- DISEASE: Ciliary dyskinesia, primary, 29 (CILD29) [MIM:615872]: A disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. CILD29 patients do not exhibit situs inversus, a congenital abnormality in which visceral organs are opposite to their normal positions (situs solitus) due to lateral transposition. {ECO:0000269|PubMed:24747639, ECO:0000269|PubMed:26777464}. Note=The disease is caused by mutations affecting the gene represented in this entry. Marked reduction of cilia in multiciliate cells due to defective mother centriole generation and placement. Remaining cilia correctly express axonemal motor proteins, are motile and do not show beating defects. Defects are probably caused by a strong reduction in the number of multiple motile cilia covering the cell surface in respiratory epithelial cells (PubMed:24747639). {ECO:0000269|PubMed:24747639}.;
Recessive Scores
- pRec
- 0.195
Intolerance Scores
- LoFtool
- 0.605
- RVIS EVS
- 0.48
- RVIS percentile EVS
- 79.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.812
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |