BSCL2

Chr 11ARAD

BSCL2 lipid droplet biogenesis associated, seipin

Also known as: GNG3LG, HMN5, HMN5C, HMND13, PELD, SPG17

NCBI Gene: 26580 ENSG00000168000 UniProt: Q96G97 OMIM: 606158

Seipin is an endoplasmic reticulum transmembrane protein that plays a crucial role in lipid droplet formation and maturation, which are essential for lipid and energy homeostasis. Mutations cause a spectrum of disorders including congenital generalized lipodystrophy type 2 (Berardinelli-Seip syndrome), progressive encephalopathy with or without lipodystrophy, distal hereditary motor neuronopathy, and Silver spastic paraplegia syndrome. The gene shows both autosomal recessive and autosomal dominant inheritance patterns depending on the specific condition.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 1.014 OMIM phenotypes

Clinical Summary— BSCL2

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Gene-Disease Validity (ClinGen)

distal hereditary motor neuropathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

62 unique Pathogenic / Likely Pathogenic· 331 VUS of 673 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — BSCL2

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?

1.01LOEUF

pLI 0.000

Z-score 1.53

OE 0.68 (0.47–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.26Z-score

OE missense 0.95 (0.86–1.06)

248 obs / 259.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.47–1.01)

0≤0.351.4

Missense OE?0.95 (0.86–1.06)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 18 / 26.5Missense obs/exp: 248 / 259.8Syn Z: -0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBSCL2-related lipodystrophy, congenital generalisedLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6356th %ile

GOF

0.6345th %ile

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

GOFIto and Suzuki (2007) concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the unfolded protein response, cell death, and neurodegeneration.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 18585921 ↗

ClinVar Variant Classifications

673 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic26

VUS331

Likely Benign204

Benign16

Conflicting58

Pathogenic

Likely Pathogenic

331

VUS

204

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	3	4	0	36
Likely Pathogenic	23	3	0	0	26
VUS	12	291	21	7	331
Likely Benign	1	17	86	100	204
Benign	0	2	14	0	16
Conflicting	—				58
Total	65	316	125	107	671

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap BSCL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →