CFAP298
protein-codingcilia and flagella associated protein 298, the group of Cilia and flagella associated|Axonemal dynein assembly factors
Gene summary
This gene encodes a protein that plays a critical role in dynein arm assembly and motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Naturally occuring readthrough transcription occurs from this locus to the downstream t-complex 10 like (TCP10L) gene. [provided by RefSeq, Apr 2017]
- C21orf48
- C21orf59
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014211
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016575
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014211
Submitter: ClinGen
Cilia and flagella associated protein 298 (*CFAP298*), also known as *C21orf59*, was first reported in relation to primary ciliary dyskinesia in 2013 (PMID: 24094744). Four unrelated individuals were reported with biallelic *CFAP298* truncating variants and a classical PCD phenotype with reduced nasal nitric oxide, recurrent chest infections and both outer and inner dynein arm defects. Situs inversus was detected in all 3 patients carrying the homozygous c.735C>G (p.Tyr245Ter) nonsense variant. Haplotype analysis of these patients indicated that this mutation is located within a shared haplotype and strongly suggested a founder effect, consistent with the high allele frequency of 0.001736 observed in among control individuals in the Ashkenazi Jewish population. The fourth published patient was compound heterozygous for the truncating variants c.292C>T (p.Arg98Ter), and c.792_795delTTTA (p.Tyr264Ter). Injection of human C21orf59 mRNA bearing the c.792_795delTTTA (p.Tyr264Ter) mutation failed to rescue cilia motility in zebrafish (PMID: 24094744). This curation identified but did not score an additional published proband from a cohort with laterality defects, due to the absence of additional clinical details to evaluate the full phenotype (PMID: 34215651). This curation was also informed by the identification of an additional proband within a French PCD cohort with biallelic variants in *CFAP298* and a phenotype matching the published cases. The mechanism of disease appears to be biallelic loss-of-function in *CFAP298*, however, there is an urgent need for publication of additional cases to better understand the spectrum of disease-causing variants and clinical features. This gene-disease relationship is also supported by experimental evidence that the *C21orf59* transcript is strongly expressed in ciliated tissues of the zebrafish trunk, including the pronephric ducts and spinal canal (PMID: 24094744). Morpholino knockdown of the *C21orf59* gene in zebrafish resulted in loss of dynein arms and a strong ciliopathy phenotype, including those involving pronephric cysts, axis curvature, left-right asymmetry defects, and hydrocephalus. Moreover, *C21orf59* mRNA expression in ciliated tissues is eliminated by *Foxj1a* knockdown, indicating that *C21orf59* expression is controlled by this ciliogenic transcription factor. *C21orf59*/*Kurly* (*Kur*) was also required for proper cilia polarization needed for the movement of the ECF in the zebrafish kidney and the larval skin of *Xenopus laevis* (PMID: 26904945). Motility- impaired *Chlamydomonas* mutants showed increased abundance of C21orf59/FBB18 protein suggesting that it is induced or stabilized when cilia motility is impaired (PMID: 24094744). In summary, there is moderate evidence to support the gene-disease relationship of *CFAP298* with primary ciliary dyskinesia 26 (MONDO:0014211). While more evidence is needed to establish this relationship more definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 10th, 2023 (SOP Version 9).
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Pulmonary
Intervention: Allergy/Immunology/Infectious; Cardiovascular; 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; The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CFAP298 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021254.4. 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 | 46 | 1 | 48 | ||
| missense | 1 | 55 | 4 | 60 | ||
| nonsense | 4 | 2 | 1 | 7 | ||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 3 | 2 | 7 | ||
| splice donor/acceptor (+/-2bp) | 1 | 4 | 5 | |||
| Total | 7 | 6 | 64 | 50 | 1 | 128 |
Highest pathogenic variant AF is 0.00022054788
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_067077.1 | 7 | MANE Select | |
| Ensembl | ENSP00000290155.3 | 7 | MANE Select | |
| RefSeq | NP_001337263.1 | 5 | Standard | |
| RefSeq | NP_001337264.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cfap298 | Danio rerio | Structure: ciliated olfactory receptor neuron Quality: absent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of cilium movement
- cilium assembly
Molecular Function
- protein binding
Cellular Component
- nucleus
- cytosol
- cytoskeleton
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000290155
- Coding exons
- 7
- Length
- 20788
- Individuals with no LoFs
- 125632
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 115
- Defined
- 125747
- p
- 0.000457
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.378 | 148 | 162 | 0.916 | 0.00000845 | 1898 |
| Missense (PolyPhen) | 38 | 44.634 | 0.85137 | 519 | ||
| Synonymous | -0.990 | 76 | 65.8 | 1.16 | 0.00000414 | 526 |
| Loss of Function | 1.38 | 12 | 18.4 | 0.653 | 0.00000103 | 203 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0.0021 | 0.0021 | notable |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.00060 | 0.00060 | rare |
| European (Non-Finnish) | 0.00049 | 0.00047 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in motile cilium function, possibly by acting on outer dynein arm assembly (PubMed:24094744). Seems to be important for initiation rather than maintenance of cilium motility (By similarity). Required for correct positioning of the cilium at the apical cell surface, suggesting an additional role in the planar cell polarity (PCP) pathway (By similarity). May suppress canonical Wnt signaling activity (By similarity). {ECO:0000250|UniProtKB:Q6DRC3, ECO:0000269|PubMed:24094744}.;
- Disease
- DISEASE: Ciliary dyskinesia, primary, 26 (CILD26) [MIM:615500]: 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. Patients may exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. {ECO:0000269|PubMed:24094744}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cilia in nasal epithelia show the absence of both outer and inner dynein- arm components and complete paralysis.;
Intolerance Scores
- RVIS EVS
- -0.07
- RVIS percentile EVS
- 48.35
Essentials
- Essential (gene trap)
- E