CEP250

protein-coding

centrosomal protein 250

Gene summary

This gene encodes a core centrosomal protein required for centriole-centriole cohesion during interphase of the cell cycle. The encoded protein dissociates from the centrosomes when parental centrioles separate at the beginning of mitosis. The protein associates with and is phosphorylated by NIMA-related kinase 2, which is also associated with the centrosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

Previous symbols:

CEP2

MANE transcript

NM_007186.6

Inheritance

ClinVar variants

P:124U:860B:536

Top phenotype

Cone-rod dystrophy and hearing loss 2

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr20:35,455,164-35,519,280

External References & Databases

Ensembl (ENSG00000126001)

Transcript & Mutation Effects

hg38 • Region Span ~64.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone-rod dystrophy and hearing loss 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0020780

Submitter: Ambry Genetics

cone-rod dystrophy and hearing loss 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020780

Submitter: G2P

male infertility with azoospermia or oligozoospermia due to single gene mutationNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0018393

Submitter: King Faisal Specialist Hospital and Research Center

Convincing evidence disputing a role for this gene is this disease has arisen since the initial report identifying a gene for Cone-rod dystrophy and hearing loss 2. OMIM listing of CEP250- related retinal dystrophy with hearing loss is based on a few families with missense or compound missense and truncating variants, and the one family with a homozygous nonsense variant was also homozygous for a nonsense variant in an established retinal dystrophy-related gene C2orf71. Alhathal et al., 2020 (PMID: 32719396) four different homozygous missense or truncating variants with no evidence of retinal dystrophy or hearing loss, which is consistent with the male infertility phenotype observed in Cep250−/−mice (https://www.mousephenotype.org/data/ genes/MGI:108084).

cone-rod dystrophy and hearing loss 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020780

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: Franklin by Genoox

In a consanguineous family with nonsyndromic RP DNA analysis revealed a homozygous mutation (c.562C>T, p.R188*) in the CEP250 gene https://doi.org/10.1002/humu.23759

cone-rod dystrophy and hearing loss 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020780

Submitter: ClinGen

CEP250 was first reported in relation to autosomal recessive cone-rod dystrophy and hearing loss 2 in 2014 (Khateb et al., PMID: 24780881). Affected individuals are reported with retinal dystrophy, including cone-rod dystrophy, and hearing loss. Both features present with varying severity and age of onset. At least 10 nonsense and frameshift variants that have been reported in 6 probands in 4 publications (PMIDs: 24780881, 29718797, 30459346, 39610034) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence was reached (12 pts.). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by two knockout mouse models and expression data. One knockout mouse model showed decreasing ERGs with age, increased ABR hearing thresholds, and decreased outer nuclear layer on retinal histology (PMID: 36857066). Another model showed increased ABR threshold at one frequency and OHC degeneration that was more robust in the high frequency region of the basal turn of the cochlea (PMID: 37759551). CEP250 was shown to be expressed in the inner hair cells, outer hair cells, pillar cells, supporting cells and spiral ganglion, and knockout mice showed lack of expression in these structures (PMID: 37759551). Of note, this curation also included one publication reporting autosomal recessive nonsyndromic hearing loss; however, it was determined that features of retinal dystrophy could not be fully ruled out and that the association with purely nonsyndromic hearing loss was limited (PMID: 37759551). In summary, there is definitive evidence supporting the relationship between CEP250 and autosomal recessive cone-rod dystrophy and hearing loss 2. 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 Hearing Loss GCEP on the meeting date July 16th, 2025 (SOP Version 11).

cone-rod dystrophy and hearing loss 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020780

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cone-rod dystrophy and hearing loss 2AR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: The condition can involve early-onset hearing impairment, and early recognition and treatment may improve outcomes, including speech and language development

Refs: 24780881; 28005958; 29718797; 30459346

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEP250 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 1551

not specifiedTotal: 493

CEP250-related disorderTotal: 120

Cone-rod dystrophy and hearing loss 2Total: 37

Retinal dystrophyTotal: 15

Optic atrophyTotal: 4

Usher syndromeTotal: 2

Monogenic hearing lossTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007186.6. 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 clinvar	461 clinvar	6 clinvar	475
missense		1 clinvar	830 clinvar	58 clinvar	11 clinvar	900
nonsense	29 clinvar	21 clinvar	5 clinvar			55
start loss						0
frameshift	39 clinvar	16 clinvar	6 clinvar			61
splice donor/acceptor (+/-2bp)	2 clinvar	16 clinvar	11 clinvar			29
Total	70	54	860	519	17	1520

Highest pathogenic variant AF is 0.0003270709

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007186.6	RefSeq	NP_009117.2	32	MANE Select
ENST00000397527.6	Ensembl	ENSP00000380661.1	32	MANE Select
NM_001318219.1	RefSeq	NP_001305148.1	19	Standard
ENST00000397524.5	Ensembl	ENSP00000380658.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mesodermal Commitment Pathway
Regulation of PLK1 Activity at G2/M Transition
Recruitment of mitotic centrosome proteins and complexes
Loss of Nlp from mitotic centrosomes
Loss of proteins required for interphase microtubule organization from the centrosome

Biological Process

G2/M transition of mitotic cell cycle
mitotic cell cycle
protein localization
regulation of G2/M transition of mitotic cell cycle
centriole-centriole cohesion

Molecular Function

protein binding
protein C-terminus binding
protein kinase binding
protein domain specific binding

Cellular Component

centrosome
centriole
microtubule organizing center
cytosol
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397527
Coding exons: 32
Length: 56820
Individuals with no LoFs: 125450
Homozygous LoFs: 0
Heterozygous LoFs: 298
Defined: 125748
p: 0.00119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.33	1136	1.27e+3	0.895	0.0000726	15721
Missense (PolyPhen)		332	394.36	0.84187		5341
Synonymous	2.44	451	522	0.864	0.0000266	4791
Loss of Function	5.17	77	144	0.535	0.00000809	1476

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00065	0.00062	rare
Latino/Admixed American	0.0019	0.0019	notable
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00088	0.00087	rare
Finnish	0.0032	0.0027	notable
European (Non-Finnish)	0.0010	0.0010	notable
South Asian	0.00066	0.00062	rare
Other	0.0018	0.0018	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably plays an important role in centrosome cohesion during interphase.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.939
RVIS EVS: -0.77
RVIS percentile EVS: 13.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

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