BBS12
protein-codingBardet-Biedl syndrome 12, the group of Chaperonins
Gene summary
The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]
- C4orf24
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:1040045
Submitter: ClinGen
The *BBS12* gene was first identified as a disease-related locus in a 2007 study mapping the Bardet Biedl syndrome phenotype in two consanguineous families to a homozygous region on chromosome 4q26-q27 (Stoetzel C, et al., 2007, PMID: 17160889). *BBS12* encodes a predicted chaperonin-like protein that exists specifically in vertebrates, and forms a complex with BBS6 and BBS10 that functions to mediate the assembly of the BBSome, a complex that performs vesicle transport to primary cilia and contributes to adipocyte differentiation (PMID: 17160889, PMID: 20080638). Bardet-Biedl syndrome 12 (MIM#: 615989) is an autosomal recessive disorder characterized by variable expressivity and phenotypes such as retinal dystrophy, mental retardation, obesity, polydactyly, and/or renal abnormalities. The underlying mechanism is biallelic loss-of function variants in the *BBS12* gene, with the mutation spectrum including predominantly missense, nonsense, and frameshift variants. This curation has collected and scored data from 2 consanguineous families and 1 isolated individual with 4 unique variants (PMID: 17160889, PMID: 20648243, PMID: 36574078). Additional genetic evidence was available in the literature but was not included as the maximum score for this category had already been reached. Experimental evidence for the gene-disease relationship included a zebrafish model with suppression of *bbs12* expression that exhibited defects in gastrulation and movement such as short body axis, broader somites, kinking of the notochord, and dorsal thinning, similar to the phenotypes caused by silencing of other *BBS* gene orthologs (PMID: 17160889). The participation of the BBS12 protein in a complex with BBS6 and BBS10 was also scored as protein interaction data (PMID: 20080638). In summary, *BBS12* is definitively associated with BBS12-related ciliopathy, in which one of the major features is retinal dystrophy. This 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 clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 4th, 2024 (SOP version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014440
Submitter: Labcorp Genetics (formerly Invitae)
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 BBS12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152618.3. 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 | 4 | 298 | 3 | 305 | ||
| missense | 2 | 27 | 384 | 23 | 3 | 439 |
| nonsense | 18 | 33 | 1 | 52 | ||
| start loss | 3 | 3 | ||||
| frameshift | 57 | 68 | 1 | 126 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 77 | 129 | 394 | 321 | 6 | 927 |
Highest pathogenic variant AF is 0.00009912534
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689831.2 | 1 | MANE Select | |
| Ensembl | ENSP00000319062.3 | 1 | MANE Select | |
| RefSeq | NP_001171478.1 | 1 | Standard | |
| Ensembl | ENSP00000398912.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bbs12 | Danio rerio | Structure: whole organism Quality: decreased length 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
- intraciliary transport
- eating behavior
- photoreceptor cell maintenance
- negative regulation of fat cell differentiation
- chaperone-mediated protein complex assembly
Molecular Function
- protein binding
- ATP binding
Cellular Component
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000542236
- Coding exons
- 1
- Length
- 12242
- Individuals with no LoFs
- 125655
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 93
- Defined
- 125748
- p
- 0.000370
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.336 | 348 | 366 | 0.951 | 0.0000183 | 4633 |
| Missense (PolyPhen) | 97 | 109.01 | 0.88987 | 1431 | ||
| Synonymous | 1.13 | 124 | 141 | 0.879 | 0.00000732 | 1411 |
| Loss of Function | 1.70 | 14 | 22.7 | 0.616 | 0.00000123 | 300 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00063 | 0.00062 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. As part of the TRiC complex may play 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 12 (BBS12) [MIM:615989]: 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:17160889, ECO:0000269|PubMed:20080638, ECO:0000269|PubMed:20120035, ECO:0000269|PubMed:21344540}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.173
Intolerance Scores
- LoFtool
- 0.876
- RVIS EVS
- 1.38
- RVIS percentile EVS
- 94.6
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.146
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |