Congenital generalized lipodystrophy type 2

Summary

Congenital generalized lipodystrophy type 2 (MONDO:0010020) is a disease caused by BSCL2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: BSCL2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 166

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital generalized lipodystrophy type 2
Mondo ID	MONDO:0010020
OMIM	269700
Orphanet	696289
DOID	DOID:0111136
UMLS	C1720863
MedGen	318593
GARD	0010212
Is cancer (heuristic)	no

Also known as: Berardinelli Seip congenital lipodystrophy type 2 · BSCL2 congenital generalised lipodystrophy (disease) · BSCL2 congenital generalized lipodystrophy (disease) · BSCL2-related Brunzell syndrome · CGL2 · congenital generalised lipodystrophy (disease) caused by mutation in BSCL2 · congenital generalized lipodystrophy (disease) caused by mutation in BSCL2 · lipodystrophy, congenital generalized, type 2

Data availability: 166 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › congenital generalized lipodystrophy › congenital generalized lipodystrophy type 2

Related subtypes (4): congenital generalized lipodystrophy type 1, congenital generalized lipodystrophy type 3, congenital generalized lipodystrophy type 4, lipodystrophy, congenital generalized, type 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

166 retrieved; paginated sample, class counts are floors:

78 uncertain significance, 36 conflicting classifications of pathogenicity, 18 pathogenic, 9 likely pathogenic, 8 likely benign, 6 pathogenic/likely pathogenic, 5 benign/likely benign, 5 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
143858	NM_001122955.4(BSCL2):c.985C>T (p.Arg329Ter)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
245977	NM_001122955.4(BSCL2):c.1006-2A>G	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372117	NM_001122955.4(BSCL2):c.766-2A>G	BSCL2	Pathogenic	criteria provided, single submitter
372120	NM_001122955.4(BSCL2):c.974dup (p.Ile326fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
393432	NM_001122955.4(BSCL2):c.631-1G>C	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424623	NM_001122955.4(BSCL2):c.844_854del (p.Ala282fs)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434545	NM_001122955.4(BSCL2):c.942dup (p.Leu315fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4532	NM_001122955.4(BSCL2):c.493_494insAA (p.Met165fs)	BSCL2	Pathogenic	criteria provided, single submitter
4532106	NM_001122955.4(BSCL2):c.630+1G>T	BSCL2	Pathogenic	criteria provided, single submitter
4534	BSCL2, 258-BP DEL/12-BP INS	BSCL2	Pathogenic	no assertion criteria provided
4535	NM_001122955.4(BSCL2):c.509_513del (p.Tyr170fs)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4536	NM_001122955.4(BSCL2):c.517dup (p.Thr173fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4537	NM_001122955.4(BSCL2):c.604C>T (p.Arg202Ter)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4540	NM_001122955.4(BSCL2):c.828del (p.Tyr277fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4545	NM_001122955.4(BSCL2):c.1015C>T (p.Arg339Ter)	BSCL2	Pathogenic	criteria provided, single submitter
4546	NM_001122955.4(BSCL2):c.757G>T (p.Glu253Ter)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4687517	NM_001122955.4(BSCL2):c.324_325del (p.Ser109fs)	BSCL2	Pathogenic	criteria provided, single submitter
549713	NM_001122955.4(BSCL2):c.404+1G>T	BSCL2	Pathogenic	no assertion criteria provided
549714	NM_001122955.4(BSCL2):c.759_760del (p.Asn254fs)	BSCL2	Pathogenic	no assertion criteria provided
549716	NM_001122955.4(BSCL2):c.402C>G (p.Tyr134Ter)	BSCL2	Pathogenic	no assertion criteria provided
844412	NM_001122955.4(BSCL2):c.486+1G>A	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
947075	NM_001122955.4(BSCL2):c.1361_1386del (p.Arg454fs)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372119	NM_001122955.4(BSCL2):c.864-2A>G	HNRNPUL2-BSCL2	Pathogenic	criteria provided, single submitter
4539	NM_001122955.4(BSCL2):c.826G>C (p.Ala276Pro)	HNRNPUL2-BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
3767981	NM_016188.5(ACTL6B):c.1113+1G>T	ACTL6B	Likely pathogenic	criteria provided, single submitter
1685254	NM_001122955.4(BSCL2):c.486+1G>T	BSCL2	Likely pathogenic	criteria provided, single submitter
1687147	NM_001122955.4(BSCL2):c.862dup (p.Arg288fs)	BSCL2	Likely pathogenic	no assertion criteria provided
3383977	NM_001122955.4(BSCL2):c.825dup (p.Ala276fs)	BSCL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599919	NM_001122955.4(BSCL2):c.1048C>T (p.Arg350Ter)	BSCL2	Likely pathogenic	criteria provided, single submitter
3599928	NM_001122955.4(BSCL2):c.766-1G>A	BSCL2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BSCL2	Definitive	Autosomal recessive	congenital generalized lipodystrophy type 2	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2
ACTL6B	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ACTL6B	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	gencc,clinvar
ACTL6B	HGNC:160	ENSG00000077080	O94805	Actin-like protein 6B	clinvar
HNRNPUL2-BSCL2	HGNC:49189	ENSG00000234857		HNRNPUL2-BSCL2 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
ACTL6B	Actin-like protein 6B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BSCL2	Other/Unknown	no		Seipin
ACTL6B	Other/Unknown	no		Actin, Actin_CS, ATPase_NBD
HNRNPUL2-BSCL2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pituitary gland	1
primary visual cortex	1
superior frontal gyrus	1
cerebellar hemisphere	1
cortical plate	1
right hemisphere of cerebellum	1
islet of Langerhans	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
ACTL6B	164	broad	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere
HNRNPUL2-BSCL2	134		yes	stromal cell of endometrium, ventricular zone, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTL6B	4,543
BSCL2	1,503
HNRNPUL2-BSCL2	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BSCL2	Q96G97	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTL6B	O94805	91.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.015	ACTL6B
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.015	ACTL6B
RMTs methylate histone arginines	1	146.4×	0.015	ACTL6B
Transcriptional regulation by RUNX1	1	146.4×	0.015	ACTL6B
Chromatin organization	1	81.6×	0.021	ACTL6B
Chromatin modifying enzymes	1	72.3×	0.021	ACTL6B
RNA Polymerase II Transcription	1	22.5×	0.057	ACTL6B
Gene expression (Transcription)	1	17.8×	0.063	ACTL6B
Generic Transcription Pathway	1	15.1×	0.066	ACTL6B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid droplet formation	1	495.6×	0.011	BSCL2
lipid droplet organization	1	468.1×	0.011	BSCL2
negative regulation of lipid catabolic process	1	421.3×	0.011	BSCL2
neuron maturation	1	401.2×	0.011	ACTL6B
regulation of G0 to G1 transition	1	337.0×	0.011	ACTL6B
regulation of nucleotide-excision repair	1	300.9×	0.011	ACTL6B
lipid storage	1	271.8×	0.011	BSCL2
regulation of mitotic metaphase/anaphase transition	1	247.8×	0.011	ACTL6B
positive regulation of T cell differentiation	1	227.7×	0.011	ACTL6B
dendrite development	1	195.9×	0.011	ACTL6B
positive regulation of myoblast differentiation	1	183.2×	0.011	ACTL6B
positive regulation of stem cell population maintenance	1	172.0×	0.011	ACTL6B
positive regulation of double-strand break repair	1	172.0×	0.011	ACTL6B
regulation of G1/S transition of mitotic cell cycle	1	153.2×	0.011	ACTL6B
negative regulation of cell differentiation	1	142.8×	0.011	ACTL6B
positive regulation of cell differentiation	1	133.8×	0.011	ACTL6B
lipid catabolic process	1	122.1×	0.012	BSCL2
fat cell differentiation	1	90.6×	0.015	BSCL2
positive regulation of cold-induced thermogenesis	1	81.8×	0.015	BSCL2
chromatin organization	1	49.6×	0.024	ACTL6B
chromatin remodeling	1	36.5×	0.031	ACTL6B
nervous system development	1	23.0×	0.047	ACTL6B
positive regulation of cell population proliferation	1	16.8×	0.061	ACTL6B
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ACTL6B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BSCL2	0	0
ACTL6B	0	0
HNRNPUL2-BSCL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	BSCL2, ACTL6B, HNRNPUL2-BSCL2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BSCL2	0	—
ACTL6B	0	—
HNRNPUL2-BSCL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.