GeneBe

BBS2

protein-coding

Bardet-Biedl syndrome 2, the group of BBSome

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 severe pigmentary retinopathy, 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 forms a multiprotein BBSome complex with seven other BBS proteins.[provided by RefSeq, Oct 2014]

Previous symbols:
  • BBS

MANE transcript

NM_031885.5

Inheritance

AR, AD

ClinVar variants

P:309U:433B:341

Top phenotype

Bardet-Biedl syndrome 2;

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr16:56,465,640-56,582,667

External References & Databases

Ensembl (ENSG00000125124)NCBI Gene (583)OMIM (606151)HGNC:967GenCCUniProt (Q9BXC9)AlphaFoldClinVar (BBS2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~117.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bardet-Biedl syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014432

Submitter: Labcorp Genetics (formerly Invitae)

BBS2-related ciliopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:1040048

Submitter: PanelApp Australia

Bardet-Biedl syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014432

Submitter: Natera

Bardet-Biedl syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014432

Submitter: Myriad Women's Health

Bardet-Biedl syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014432

Submitter: Genomics England PanelApp

retinitis pigmentosa 74DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014692

Submitter: G2P

Bardet-Biedl syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014432

Submitter: Ambry Genetics

Bardet-Biedl syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014432

Submitter: G2P

BBS2-related ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1040048

Submitter: ClinGen

*BBS2* was first reported in relation to autosomal recessive Bardet-Biedl Syndrome in 2001 (Nishimura et al., PMID: 11285252). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *BBS2* loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 2 (MIM#: 606151) or retinitis pigmentosa 74 (MIM#: 616562), while the phenotypic variability between the two groups of cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *BBS2* variants have been lumped into a single disease entity, referred to as *BBS2*-related ciliopathy. Nine unique variants (two missense, three nonsense, one frameshift, and three splicing) that have been reported in thirteen probands in five publications (PMIDs: 11567139, 11285252, 24608809, 21052717, 33777945) are included in this curation. 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 biallelic loss-of-function. This gene-disease association is also supported by data from ProteinAtlas that *BBS2* is non-specifically expressed in the retina as well as many other tissues, consistent with the clinical heterogeneity of Bardet-Biedl syndrome (PMID: 28940711). Biochemical evidence indicates that the protein encoded by the *BBS2* gene is a component of the BBSome, a protein complex that functions in ciliogenesis and intraflagellar transport (PMID: 22072986). Tandem affinity purification followed by mass spectrometry has shown that *BBS2* forms a stable complex along with other proteins that are encoded by genes associated with Bardet-Biedl syndrome (*BBS1*, *BBS4*, *BBS5*, *BBS7*, *BBS8*, and *BBS9*, PMID: 17574030). *BBS2* homozygous knockout zebrafish without a functional copy of *BBS2* exhibit retinal degeneration and vision loss (PMID: 33324636). A *Bbs2* null mouse model recapitulated even more of the features of human patients, including obesity, retinal degeneration, renal cysts, and male infertility (PMID: 15539463). In summary, *BBS2* is definitively associated with autosomal recessive BBS2-related 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 Retina Gene Curation Expert Panel on March 7th, 2024 (SOP Version 10).

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

retinitis pigmentosa 74STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014692

Submitter: Labcorp Genetics (formerly Invitae)

Bardet-Biedl syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Clinical Genomic Database (CGD)

Bardet-Biedl syndrome 2;AR

Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Endocrine

Rationale: 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

Refs: 8298649; 11285252; 11567139; 16823392; 16582908; 20120035; 20301537; 20618352; 22410627; 25541840; 36356613Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BBS2 variants in ClinVar

21 Conditions Cataloged
Bardet-Biedl syndromeTotal: 932
Bardet-Biedl syndrome 2Total: 482
BBS2-related disorderTotal: 361
Retinitis pigmentosa 74Total: 210
not providedTotal: 168
not specifiedTotal: 107
Inborn genetic diseasesTotal: 77
Retinal dystrophyTotal: 46

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031885.5. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
15
clinvar
324
clinvar
1
clinvar
 344
missense
4
clinvar
31
clinvar
415
clinvar
15
clinvar
1
clinvar
 466
nonsense
21
clinvar
39
clinvar
1
clinvar
 61
start loss
1
clinvar
1
clinvar
 2
frameshift
59
clinvar
85
clinvar
1
clinvar
 145
splice donor/acceptor (+/-2bp)
14
clinvar
50
clinvar
1
clinvar
 65
Total9921043333921083

Highest pathogenic variant AF is 0.00025774792

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_031885.5RefSeqNP_114091.417MANE Select
ENST00000245157.11EnsemblENSP00000245157.517MANE Select
NM_001377456.1RefSeqNP_001364385.117Standard
ENST00000561877.2EnsemblENSP00000454986.24Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
bbs2Danio 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

  • sperm axoneme assembly
  • visual perception
  • protein localization
  • negative regulation of gene expression
  • artery smooth muscle contraction

Molecular Function

  • RNA polymerase II repressing transcription factor binding
  • protein binding

Cellular Component

  • cytosol
  • microvillus
  • membrane
  • motile cilium
  • stereocilium

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000245157
Coding exons
17
Length
53448
Individuals with no LoFs
125556
Homozygous LoFs
0
Heterozygous LoFs
192
Defined
125748
p
0.000764
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8703514000.8780.00002264752
Missense (PolyPhen)125148.280.8431781
Synonymous0.2431431470.9750.000007751426
Loss of Function1.223139.30.7900.00000262410

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.00220.0022notable
Finnish0.000880.00088rare
European (Non-Finnish)0.000910.00091rare
South Asian0.000420.00042rare
Other0.000820.00081rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization. {ECO:0000269|PubMed:17574030, ECO:0000269|PubMed:22072986}.;
Disease
DISEASE: Retinitis pigmentosa 74 (RP74) [MIM:616562]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:25541840}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0955

Intolerance Scores

LoFtool
0.233
RVIS EVS
-0.84
RVIS percentile EVS
11.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.805

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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