rs1325008761

Variant names:

• chr11-62694692-G-A
• rs1325008761
• NM_001122955.4:c.506C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000360796.10(BSCL2):​c.506C>T​(p.Pro169Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P169S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: BSCL2 ENST00000360796.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.69
• Publications: 0 publications found

Genes affected

BSCL2 (HGNC:15832): (BSCL2 lipid droplet biogenesis associated, seipin) This gene encodes the multi-pass transmembrane protein 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, Mar 2011]

HNRNPUL2-BSCL2 (HGNC:49189): (HNRNPUL2-BSCL2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring HNRNPUL2 (heterogeneous nuclear ribonucleoprotein U-like 2) and BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 (seipin)) genes on chromosome 11. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360796.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BSCL2	NM_001122955.4	MANE Select	c.506C>T	p.Pro169Leu	missense	Exon 4 of 11	NP_001116427.1
	BSCL2	NM_001386027.1		c.506C>T	p.Pro169Leu	missense	Exon 5 of 12	NP_001372956.1
	BSCL2	NM_001386028.1		c.506C>T	p.Pro169Leu	missense	Exon 5 of 12	NP_001372957.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BSCL2	ENST00000360796.10	TSL:1 MANE Select	c.506C>T	p.Pro169Leu	missense	Exon 4 of 11	ENSP00000354032.5
	BSCL2	ENST00000405837.5	TSL:1	c.506C>T	p.Pro169Leu	missense	Exon 5 of 12	ENSP00000385332.1
	BSCL2	ENST00000407022.7	TSL:1	c.314C>T	p.Pro105Leu	missense	Exon 4 of 11	ENSP00000384080.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251336 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000312 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 2 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.016	D
Polyphen		0.98	D
Vest4		0.51
MutPred		0.56		Loss of loop (P = 0.0203)
MVP		0.97
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.58
gMVP		0.85
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1325008761; hg19: chr11-62462164;