CEP290

Chr 12AR

centrosomal protein 290

Also known as: 3H11Ag, BBS14, CT87, JBTS5, LCA10, MKS4, NPHP6, POC3

NCBI Gene: 80184 ENSG00000198707 UniProt: O15078 OMIM: 610142

This protein is essential for cilia formation and function, regulating early ciliogenesis steps, centrosomal recruitment of ciliary proteins, and ciliary membrane composition. Autosomal recessive mutations cause a spectrum of ciliopathies including Joubert syndrome, Leber congenital amaurosis, Meckel syndrome, Senior-Loken syndrome, and Bardet-Biedl syndrome. The pathogenic mechanism involves disrupted ciliary assembly and transport processes, particularly affecting retinal photoreceptors and other ciliated tissues.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Bardet-Biedl syndrome 14MIM #615991

Joubert syndrome 5MIM #610188

Leber congenital amaurosis 10MIM #611755

Meckel syndrome 4MIM #611134

Senior-Loken syndrome 6MIM #610189

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · CEP290-related ciliopathy · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.98

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — CEP290

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.69

OE 0.84 (0.71–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.96 (0.91–1.01)

949 obs / 991.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.71–0.98)

0≤0.351.4

Missense OE?0.96 (0.91–1.01)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 104 / 124.3Missense obs/exp: 949 / 991.0Syn Z: 0.13

Background carrier burden — how many people carry a rare variant somewhere in CEP290?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 19

3,164 rare PASS variants

Rare truncating (LoF)

1 in 98

750 rare PASS variants

Rare synonymous (reference)

1 in 65

1,063 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CEP290. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 25	1 in 110
South Asian	~43k	1 in 17	1 in 76
Remaining (unassigned)	~30k	1 in 19	1 in 110
European (Finnish)	~27k	1 in 71	1 in 200
Admixed American	~22k	1 in 19	1 in 95
African / African American	~21k	1 in 17	1 in 92
East Asian	~20k	1 in 21	1 in 95
Ashkenazi Jewish	~13k	1 in 93	1 in 210
Middle Eastern	~2,884	1 in 17	1 in 160

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 53 coding exons well covered in gnomAD exomes; exons 5, 13, 23, 32, 53 poorly covered; exons 3, 4, 7, 8, 10 and 24 more marginal. Genomes: 52 of 53 (exon 11 below).? see exons ↓