CEP104

protein-coding

centrosomal protein 104, the group of Cilia and flagella associated|TOG domain containing

Gene summary

This gene encodes a centrosomal protein required for ciliogenesis and for ciliary tip structural integrity. The mammalian protein contains three amino-terminal hydrophobic domains, two glycosylation sites, four cysteine-rich motifs, and two regions with homology to the glutamate receptor ionotropic, NMDA 1 protein. During ciliogenesis, the encoded protein translocates from the distal tips of the centrioles to the tip of the elongating cilium. Knockdown of the protein in human retinal pigment cells results in severe defects in ciliogenesis with structural deformities at the ciliary tips. Allelic variants of this gene are associated with the autosomal-recessive disorder Joubert syndrome, which is characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. [provided by RefSeq, Feb 2016]

Previous symbols:

KIAA0562

MANE transcript

NM_014704.4

Inheritance

ClinVar variants

P:61U:221B:165

Top phenotype

Intellectual developmental disorder, autosomal recessive 77

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr1:3,812,086-3,857,396

External References & Databases

Ensembl (ENSG00000116198)

Transcript & Mutation Effects

hg38 • Region Span ~45.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 25DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014770

Submitter: G2P

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The *CEP104* gene is located on chromosome 1 at 1p36.32 and encodes the centrosomal protein 104kDa. The protein contains an IFT25/APC10-like domain, two coiled-coil domains, a tumor overexpressed gene domain, four zinc finger domains, and an SxIP motif. This centrosomal protein is required for ciliogenesis and for ciliary tip structural integrity. Nagase et al. (1998) screened large proteins expressed in the brain with RT-PCR analysis and detected variable expression in all human tissues examined, with highest levels in kidney and skeletal muscle. Multiple disease entities have been reported in association with this gene, including autosomal recessive Joubert syndrome and autosomal recessive intellectual developmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism, inheritance pattern, or phenotypic spectrum. Therefore, these disease entities have been lumped into one disease entity: autosomal recessive ciliopathy: MONDO:0005308. The *CEP104* gene was first reported in relation to autosomal recessive Joubert syndrome in 2015 (Srour et al., PMID: 26477546). Patients with *CEP104* gene variants have been reported to have a distinctive cerebellar and brain stem malformation (known as the molar tooth sign), hypotonia, and developmental delays which are the three primary features of Joubert syndrome. In addition, individuals with *CEP104* variants have also been reported to have oculomotor apraxia and intellectual disability. At least 9 variants (nonsense, frameshift, splice site) have been reported in 9 probands across 4 publications (PMIDs: 26477546, 31625690, 34196201, 35359234 included in this curation). The mechanism of pathogenicity is known to be loss of function. A maximum score of 12 pts. genetic evidence was reached, considering case-level data and segregation data. This gene-disease relationship is also supported by expression studies, functional studies, in vitro assays in non-patient cells, and animal models. The scored expression data include the detection of cloned *CEP104* (known as Glybp) in rat cortex, hippocampus, cerebellum, and brainstem tissue (Kumar et al., PMID: 7488117). In addition, another expression study noted cloned human *CEP104* (known as KIAA0562) in all human tissues examined, with highest levels in kidney and skeletal muscle (Nagase et al., PMID: 9628581). The scored functional evidence involves RNAi experiments with *CEP104*-depleted cultures of human RPE1 retinal pigment epithelial cells to demonstrate a loss of *CEP104* staining at the tip of the primary cilium and daughter centriole, significant reduction in cilia formation, and significant reduction in length of cilia which supports the hypothesis that *CEP104* is required for ciliogenesis (Satish Tammana, et al., PMID: 23970417). Frikstad et al. showed that *CEP104* silencing in zebrafish causes cilia-related manifestations, including a shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. This study also completed in vivo and in vitro analyses of *CEP104* and its interaction with another Joubert syndrome-associated cilia tip protein, CSPP1. The loss of *CEP104* or CSPP1 in human cells leads to defective Hedgehog signaling in cilia (Frikstad et al., PMID: 31412255). A total of 4.5 pts. experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *CEP104* and autosomal recessive ciliopathy. 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 Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date May 13th, 2024 (SOP Version 11).

Joubert syndrome 25MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014770

Submitter: Ambry Genetics

Joubert syndrome 25STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014770

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 77AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 34196201; 35359234

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEP104 variants in ClinVar

17 Conditions Cataloged

Joubert syndrome 25Total: 295

not providedTotal: 176

not specifiedTotal: 166

Inborn genetic diseasesTotal: 148

CEP104-related disorderTotal: 46

Intellectual developmental disorder, autosomal recessive 77Total: 26

CEP104-related disordersTotal: 16

Joubert syndrome and related disordersTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014704.4. 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			3 clinvar	114 clinvar	2 clinvar	119
missense	1 clinvar		206 clinvar	45 clinvar	1 clinvar	253
nonsense	4 clinvar	15 clinvar	1 clinvar			20
start loss						0
frameshift	11 clinvar	16 clinvar	1 clinvar			28
splice donor/acceptor (+/-2bp)	2 clinvar	12 clinvar	10 clinvar	1 clinvar	2 clinvar	27
Total	18	43	221	160	5	447

Highest pathogenic variant AF is 0.00040422552

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014704.4	RefSeq	NP_055519.1	21	MANE Select
ENST00000378230.8	Ensembl	ENSP00000367476.3	21	MANE Select
ENST00000378223.3	Ensembl	ENSP00000367468.3	6	Standard
ENST00000378223.4	Ensembl	ENSP00000367468.3	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Molecular Function

protein binding
glycine binding
glutamate binding
thienylcyclohexylpiperidine binding

Cellular Component

spindle pole
centriole
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378230
Coding exons: 21
Length: 45134
Individuals with no LoFs: 125617
Homozygous LoFs: 0
Heterozygous LoFs: 131
Defined: 125748
p: 0.000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.444	503	532	0.946	0.0000312	6046
Missense (PolyPhen)		144	176.07	0.81784		2011
Synonymous	1.65	171	201	0.852	0.0000126	1737
Loss of Function	3.05	28	51.7	0.542	0.00000291	604

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00027	0.00026	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00016	0.00016	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00078	0.00078	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for ciliogenesis and for structural integrity at the ciliary tip. {ECO:0000269|PubMed:23970417}.;
Disease: DISEASE: Joubert syndrome 25 (JBTS25) [MIM:616781]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS25 clinical manifestations appear to be confined to the neurologic system. JBTS25 inheritance is autosomal recessive. {ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: -0.15
RVIS percentile EVS: 42.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium