rs137852975

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001122955.4(BSCL2):c.757G>T(p.Glu253*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,002 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E253E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BSCL2
NM_001122955.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 3.46

Publications

14 publications found

Variant links:

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]

BSCL2 links:

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]

HNRNPUL2-BSCL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-62692671-C-A is Pathogenic according to our data. Variant chr11-62692671-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BSCL2	NM_001122955.4 link	c.757G>T	p.Glu253*	stop_gained	Exon 5 of 11	ENST00000360796.10	NP_001116427.1	Q96G97-4A0A024R540

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BSCL2	ENST00000360796.10 link	c.757G>T	p.Glu253*	stop_gained	Exon 5 of 11	1	NM_001122955.4	ENSP00000354032.5	Q96G97-4
HNRNPUL2-BSCL2	ENST00000403734.2 link	n.*808G>T		non_coding_transcript_exon_variant	Exon 18 of 24	2		ENSP00000456010.1	H3BQZ7
HNRNPUL2-BSCL2	ENST00000403734.2 link	n.*808G>T		3_prime_UTR_variant	Exon 18 of 24	2		ENSP00000456010.1	H3BQZ7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251376

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital generalized lipodystrophy type 2

Pathogenic:2

Jan 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1+PM2_Supporting+PM3_Strong -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu189*) in the BSCL2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BSCL2 are known to be pathogenic (PMID: 11479539, 23564749). This variant is present in population databases (rs137852975, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with Berardinelli-Seip congenital lipodystrophy (PMID: 18057387, 19041432, 19762912, 24778225, 27612026). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Glu253*. ClinVar contains an entry for this variant (Variation ID: 4546). For these reasons, this variant has been classified as Pathogenic. -

Berardinelli-Seip congenital lipodystrophy

Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

PhyloP100

3.5

Vest4

0.91

GERP RS

5.3

PromoterAI

-0.011

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs137852975

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over