BSCL2
protein-codingBSCL2 lipid droplet biogenesis associated, seipin
Gene summary
This gene encodes the multi-pass transmembrane protein seipin. This protein localizes to the endoplasmic reticulum and may be important for lipid droplet morphology. Mutations in this gene have been associated with congenital generalized lipodystrophy type 2 or Berardinelli-Seip syndrome, a rare autosomal recessive disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. Naturally occurring read-through transcription occurs between this locus and the neighboring locus HNRNPUL2 (heterogeneous nuclear ribonucleoprotein U-like 2).[provided by RefSeq, Jul 2024]
- GNG3LG
- SPG17
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018894
Submitter: ClinGen
In 2001, the BSCL2 locus was mapped to chr11q12-q14 in one large English family with autosomal dominant Silver syndrome (SS) (PMID: 11389484). Evidence for linkage to this locus was later established in families with dominant distal hereditary motor neuropathy (dHMN-V) and Charcot-Marie-Tooth neuropathy (CMT2) (PMID: 13680364, PMID: 14981520, PMID: 15242882). The BSCL2 gene comprises 10 coding and one non-coding exons, and encodes seipin, a transmembrane protein localized in the endoplasmic reticulum. Two hot spot missense variants, p.Asn88Ser and p.Ser90Leu, within the N-glycosylation site of seipin segregated in all tested families (PMID: 15242882, PMID: 32489946, PMID: 24604904, PMID: 23553728). In vitro studies using mutant transfected cells showed altered glycosylation (PMID: 17387721, PMID: 28553203). Two other variants affecting these same residues were later identified by exome sequencing, a de novo p.Asn88Thr (PMID: 32108980) and p.Ser90Trp (PMID: 23142943). Because of the wide range of phenotypes presenting in patients carrying the same variant even within the same family (PMID: 15732094), the BSCL2-related neurological disorders were collectively referred to as seipinopathies. These represent a continuous spectrum including distal hereditary motor neuropathy (dHMN) type V, Silver syndrome, variants of Charcot-Marie-Tooth neuropathy type 2, and spastic paraplegia 17 (PMID: 20301484). The onset of symptoms ranges from early childhood to late adulthood. Hand muscle involvement is the major feature, with involvement of both upper and lower motor neurons, foot deformities, and usually absence of paresthesia, sensory loss, and sphincter disturbances. Disease progression is slow in the majority of cases, and penetrance is incomplete (PMID: 15732094, PMID: 20301484). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Sepin is expressed in a number of tissues (PMID: 14981520, PMID: 11479539). Immunohistochemical analysis showed a high level of expression in cortical neurons and motor neurons of the spinal cord (PMID: 18585921, PMID: 17387721). The mechanism of disease is heterozygous toxic gain of function. Expression of the BSCL2 mutants, N88S and S90L resulted in the accumulation of toxic aggregates in cells and activation of autophagy, an emerging common pathomechanism in inherited peripheral neuropathies (PMID: 25832430, PMID: 23470542, PMID: 17387721, PMID: 28553203). Further evidence for altered function in non-human cells and in cell culture models was also reported (PMID: 21750110, PMID: 18585921). This gene-disease association is further supported by two transgenic mouse models (PMID: 21750110, PMID: 23470542). These models recapitulate many of the phenotypes reminiscent of seipinopathies. Of note, this gene has also been implicated in autosomal recessive disorders with no neuropathy phenotype that will be assessed separately. In summary, BSCL2 gene is DEFINITIVELY associated with autosomal dominant distal hereditary motor neuropathy (dHMN). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0010043
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015353
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014402
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010020
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014402
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0006573
Submitter: ClinGen
Human pathogenic variants in the Berardinelli-Seip congenital lipodystrophy 2 (*BSCL2*) gene, which encodes a protein called seipin, were first reported in association with congenital generalized lipodystrophy 2 (CGL2) in 2001 (Magre et al, PMID:11479539). We have curated the inheritance pattern for *BSCL2*- related lipodystrophy as autosomal recessive mode of inheritance because, a recessive mode of inheritance has consistently been reported (PMIDs: Jin et al, 18057387, Costa-Riquetto et al, 34033296) Bi-allelic loss-of-function variants, including nonsense, splice site, frame shift and small deletions in the *BSCL2* gene have been reported in individuals with near- complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, early onset of diabetes, often mild intellectual disability, and in very rare cases, inherited neurological involvement (Celia’s encephalopathy/progressive encephalopathy [PELD], which can also be found in the absence of CGL and is usually caused by variants causing loss of exon 7) (PMIDs: 33916074, 34033296, 29478747, 27144933). Heterozygosity for certain BSCL2 variants believed to cause misfolding of seipin has been implicated in autosomal dominant neurological disorders including Silver spastic paraplegia and distal hereditary motor neuropathy, which do not appear to affect fat metabolism or distribution (PMID:16427281,14981520,18612770). At least 30 pathogenic variants (primarily frameshift, nonsense or splice site) in the *BSCL2* gene have been reported in humans with CGL2. Variants in this gene have been curated in at least 7 probands in 6 publications (PMIDs: 23430896, 18057387, 35351089, 30266686, 30864635, 23659685), with cases presenting as CGL2. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene-disease relationship is supported by multiple knockout mouse models that exhibit a similar phenotype and cellular studies on its role in lipid droplet formation (PMID:23989774,18458148,23680914,22269949). Total points for the experimental evidence are 5. The total score for genetic and experimental evidence together are 17. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism, and phenotype for variants causing congenital generalized lipodystrophy vs. those causing primary neurological conditions. Therefore, we curated *BSCL2* as a lumped curation for autosomal recessive congenital generalized lipodystrophy (OMIM: 269700) and progressive encephalopathy with or without lipodystrophy (OMIM 615924). Autosomal dominant neurological conditions including Silver spastic paraplegia syndrome (OMIM: 270685) and distal hereditary motor neuropathy (OMIM: 619112) will be curated separately in split curations. In summary, *BSCL2* is definitively associated with autosomal recessive congenital generalized lipodystrophy. 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 Monogenic Diabetes GCEP on November 13, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0006573
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0027766
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0030860
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0030860
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010043
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010020
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0016391
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014402
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010043
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010020
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Endocrine; Neurologic
Intervention: Cardiovascular; Endocrine
Rationale: Dietary measures (eg, restriction of fat intake) and medications (eg, leptin) may be beneficial; Individuals may have cardiomyopathy, and surveillance and early medical management may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BSCL2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001122955.4. 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 | 9 | 126 | 135 | |||
| missense | 3 | 5 | 294 | 19 | 3 | 324 |
| nonsense | 10 | 9 | 1 | 20 | ||
| start loss | 1 | 1 | ||||
| frameshift | 13 | 11 | 4 | 28 | ||
| splice donor/acceptor (+/-2bp) | 4 | 12 | 4 | 20 | ||
| Total | 30 | 37 | 313 | 145 | 3 | 528 |
Highest pathogenic variant AF is 0.000041819145
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001116427.1 | 11 | MANE Select | |
| Ensembl | ENSP00000354032.5 | 11 | MANE Select | |
| RefSeq | NP_001124174.2 | 8 | Standard | |
| RefSeq | NP_001372956.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Adipogenesis
Biological Process
- lipid catabolic process
- lipid storage
- lipid droplet organization
- fat cell differentiation
- negative regulation of lipid catabolic process
Molecular Function
- molecular_function
- protein binding
Cellular Component
- integral component of endoplasmic reticulum membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000433053
- Coding exons
- 11
- Length
- 19571
- Individuals with no LoFs
- 125702
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 46
- Defined
- 125748
- p
- 0.000183
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.260 | 248 | 260 | 0.955 | 0.0000160 | 2949 |
| Missense (PolyPhen) | 56 | 80.224 | 0.69805 | 894 | ||
| Synonymous | -0.450 | 110 | 104 | 1.06 | 0.00000662 | 960 |
| Loss of Function | 1.53 | 18 | 26.5 | 0.680 | 0.00000153 | 285 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00060 | 0.00060 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Is a regulator of lipid catabolism essential for adipocyte differentiation. May also be involved in the central regulation of energy homeostasis (By similarity). Necessary for correct lipid storage and lipid droplets maintenance; may play a tissue-autonomous role in controlling lipid storage in adipocytes and in preventing ectopic lipid droplet formation in non-adipose tissues. {ECO:0000250, ECO:0000269|PubMed:19278620, ECO:0000269|PubMed:21533227}.;
- Disease
- DISEASE: Spastic paraplegia 17, autosomal dominant (SPG17) [MIM:270685]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG17 is characterized by prominent amyotrophy of the hand muscles, the presence of mild to severe pyramidal tract signs and spastic paraplegia. SPG17 is a motor neuron disease overlapping with distal spinal muscular atrophy type 5. {ECO:0000269|PubMed:14981520, ECO:0000269|PubMed:17663003, ECO:0000269|PubMed:18585921, ECO:0000269|PubMed:24604904}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neuronopathy, distal hereditary motor, 5A (HMN5A) [MIM:600794]: A disorder characterized by distal muscular atrophy mainly affecting the upper extremities, in contrast to other distal motor neuronopathies. These constitute a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:14981520, ECO:0000269|PubMed:17663003}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Encephalopathy, progressive, with or without lipodystrophy (PELD) [MIM:615924]: A neurodegenerative disease characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade, hyperactive behavior, seizures, tremor and ataxic gait. Patients may show a mild or typical lipodystrophic appearance. {ECO:0000269|PubMed:23564749}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0708
- RVIS EVS
- -0.18
- RVIS percentile EVS
- 40.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.912
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |