BBS10
protein-codingBardet-Biedl syndrome 10, the group of Chaperonins
Gene summary
This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by progressive retinal degeneration, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene is likely not a ciliary protein but rather has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of other ciliary or basal body proteins. Inhibition of this protein's expression impairs ciliogenesis in preadipocytes. Mutations in this gene cause Bardet-Biedl syndrome type 10. [provided by RefSeq, Jan 2010]
- C12orf58
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014438
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014438
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014438
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014438
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0700237
Submitter: ClinGen
The *BBS10* gene was first reported in relation to autosomal retinal dystrophy in 2006 (Stoetzel et al., 2006, PMID: 16582908) as part of the clinical presentation of the multisystem ciliopathy known as Bardet-Beidl syndrome; *BBS10* variants appear to account for 20% of disease burden in Bardet-Biedl syndrome, depending on the ancestral background. The predominant retinal phenotype is BBS10-related rod-cone dystrophy. BBS10-related cone and cone-rod dystrophy have also been reported (PMIDs: 34940782, 36084042). We find that BBS10-related disease is inherited in an autosomal recessive pattern, with biallelic *BBS10* variants causing retinal dystrophy in the context of Bardet-Biedl syndrome, which may include obesity, polydactyly, renal symptoms, intellectual disability and genital abnormalities. While an affected individual’s symptoms may be variable, all reported cases to date appear to have retinal dystrophy. Because the cases with variable severity of syndromic presentation, including non-syndromic cases (PMID: 36084042), all exhibit a recessive mode of inheritance and share overlapping retinal phenotypes consistent with a single spectrum of disease, these cases have been lumped into a single disease entity, BBS10-related ciliopathy. This curation has scored twelve suspected disease-causing variants (8 predicted null and 6 missense variants) that have been reported in 12 probands in 12 publications (PMIDs: 16582908, 26082521, 28143435, 37031301, 33572860, 34940782, 17106446, 26518167, 20472660, 36084042). Homozygous nonsense variants in families from multiple countries were included in the curation (PMIDs: 28143435, 17106446, 26518167) from both consanguineous and non-consanguineous families. However, missense variants have also been associated with BBS-related disease in multiple publications (PMIDs: 16582908, 26082521, 20472660). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, as multiple nonsense or frameshift variants resulting in BBS10-related disease are described in the literature (PMIDs: 28143435, 17106446, 26518167). However, missense, pre-coding and splicing variants are also reported to be associated with disease (PMIDs: 16582908, 36084042, 26082521, 20472660). Genotype-phenotype correlations between retinal dystrophy subtype (rod-cone vs. cone-rod) and variant type have not been established. The BBS10 protein is a charperonin-like molecule that mediates assembly of the BBSome, a key player in molecular transport for the cilium. Multiple BBS10 animal models support the gene-disease correlation. A seminal paper (PMID: 16582908) has documented that knockdown of *BBS10* in zebrafish embryos results in axial shortening, consistent with the syndromic phenotype seen in patients harboring disease-causing variants. A mouse knockout model of disease demonstrated severe retinal degeneration and retinal thinning (PMIDs: 26273430, 36125046). In cell culture models, BBS10 interacts with other known retinal dystrophy-causing gene products, including BBSome component BBS6 (PMID: 20080638). Multiple cell culture models reinforce the gene-disease relationship, including patient-derived cells that display ciliary defects, rescued by overexpression of wild type BBS10 (PMID: 33630762). In summary, *BBS10* is definitively associated with BBS10-related ciliopathy. While disease-causing variants are largely associated with rod-cone dystrophy in the context of Bardet-Beidl syndrome, other BBS10-related phenotypes have also been described, including cone-rod dystrophy. The association with retinal dystrophy has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This definitive classification has been approved by the ClinGen Retina GCEP on August 3rd, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014438
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014438
Submitter: Myriad Women's Health
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Endocrine
Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
Comments: Variants may modify the severity of BBS and related disorders due to variants in other BBS-associated genes
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BBS10 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024685.4. 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 | 14 | 308 | 1 | 323 | ||
| missense | 5 | 37 | 427 | 22 | 491 | |
| nonsense | 26 | 40 | 1 | 67 | ||
| start loss | 2 | 3 | 5 | |||
| frameshift | 75 | 112 | 4 | 191 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 107 | 194 | 449 | 330 | 1 | 1081 |
Highest pathogenic variant AF is 0.0009276012
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_078961.3 | 2 | MANE Select | |
| Ensembl | ENSP00000497413.1 | 2 | MANE Select | |
| Ensembl | ENSP00000535286.1 | 2 | Standard | |
| Ensembl | ENSP00000535286.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bbs10 | Danio rerio | Structure: pronephric proximal convoluted tubule Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- BBSome-mediated cargo-targeting to cilium
- Cargo trafficking to the periciliary membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- retina homeostasis
- visual perception
- regulation of protein complex assembly
- photoreceptor cell maintenance
- response to stimulus
Molecular Function
- RNA polymerase II repressing transcription factor binding
- protein binding
- ATP binding
Cellular Component
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000393262
- Coding exons
- 2
- Length
- 3969
- Individuals with no LoFs
- 125494
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 254
- Defined
- 125748
- p
- 0.00101
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0950 | 372 | 377 | 0.986 | 0.0000174 | 4727 |
| Missense (PolyPhen) | 59 | 80.978 | 0.72859 | 1056 | ||
| Synonymous | -0.167 | 140 | 138 | 1.02 | 0.00000669 | 1422 |
| Loss of Function | 0.314 | 19 | 20.5 | 0.925 | 9.01e-7 | 313 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00080 | 0.00080 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.0015 | 0.0015 | notable |
| East Asian | 0.00087 | 0.00087 | rare |
| Finnish | 0.000096 | 0.000092 | rare |
| European (Non-Finnish) | 0.0015 | 0.0015 | notable |
| South Asian | 0.00079 | 0.00078 | rare |
| Other | 0.00099 | 0.00098 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis (PubMed:20080638). Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638). Involved in adipogenic differentiation (PubMed:19190184). {ECO:0000269|PubMed:19190184, ECO:0000269|PubMed:20080638}.;
- Disease
- DISEASE: Bardet-Biedl syndrome 10 (BBS10) [MIM:615987]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:16582908, ECO:0000269|PubMed:16823392, ECO:0000269|PubMed:20080638, ECO:0000269|PubMed:20120035, ECO:0000269|PubMed:21344540, ECO:0000269|PubMed:23219996, ECO:0000269|PubMed:28808579}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.149
Intolerance Scores
- LoFtool
- 0.249
- RVIS EVS
- -0.35
- RVIS percentile EVS
- 29.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.00418
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |