rs6856

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001130702.2(BSCL2):c.803A>G(p.Lys268Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,344 control chromosomes in the GnomAD database, including 35,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2289 hom., cov: 33)

Exomes 𝑓: 0.21 ( 33596 hom. )

Consequence

BSCL2
NM_001130702.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:12

Conservation

PhyloP100: -0.198

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:

BSCL2 (HGNC:):

BSCL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010504425).

BP6

Variant 11-62690803-T-C is Benign according to our data. Variant chr11-62690803-T-C is described in ClinVar as [Benign]. Clinvar id is 128533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62690803-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BSCL2	NM_001122955.4 linkuse as main transcript	c.1137A>G	p.Glu379Glu	synonymous_variant	9/11	ENST00000360796.10	NP_001116427.1	Q96G97-4A0A024R540

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BSCL2	ENST00000360796.10 linkuse as main transcript	c.1137A>G	p.Glu379Glu	synonymous_variant	9/11	1	NM_001122955.4	ENSP00000354032.5	Q96G97-4
HNRNPUL2-BSCL2	ENST00000403734.2 linkuse as main transcript	n.*1188A>G		non_coding_transcript_exon_variant	22/24	2		ENSP00000456010.1	H3BQZ7
HNRNPUL2-BSCL2	ENST00000403734.2 linkuse as main transcript	n.*1188A>G		3_prime_UTR_variant	22/24	2		ENSP00000456010.1	H3BQZ7

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25255

AN:

152094

Hom.:

2289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.139

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.0906

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.221

Gnomad OTH

AF:

0.176

GnomAD3 exomes

AF:

0.174

AC:

42637

AN:

245200

Hom.:

4035

AF XY:

0.178

AC XY:

23701

AN XY:

132896

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.0832

Gnomad SAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.210

AC:

307367

AN:

1461132

Hom.:

33596

Cov.:

AF XY:

0.209

AC XY:

152096

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.0996

Gnomad4 AMR exome

AF:

0.136

Gnomad4 ASJ exome

AF:

0.160

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.169

Gnomad4 FIN exome

AF:

0.138

Gnomad4 NFE exome

AF:

0.230

Gnomad4 OTH exome

AF:

0.188

GnomAD4 genome

AF:

0.166

AC:

25260

AN:

152212

Hom.:

2289

Cov.:

AF XY:

0.162

AC XY:

12026

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.139

Gnomad4 ASJ

AF:

0.161

Gnomad4 EAS

AF:

0.0904

Gnomad4 SAS

AF:

0.171

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.221

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.201

Hom.:

5243

Bravo

AF:

0.163

TwinsUK

AF:

0.237

AC:

878

ALSPAC

AF:

0.228

AC:

877

ESP6500AA

AF:

0.112

AC:

492

ESP6500EA

AF:

0.220

AC:

1891

ExAC

AF:

0.177

AC:

21428

Asia WGS

AF:

0.127

AC:

443

AN:

3478

EpiCase

AF:

0.232

EpiControl

AF:

0.241

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital generalized lipodystrophy type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Isolated systolic hypertension;C4021419:Triangular shaped proximal phalanx of the thumb;C5139433:Neutrophilia in presence of infection

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Phenosystems SA

- -

Severe neurodegenerative syndrome with lipodystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Hereditary spastic paraplegia 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Neuronopathy, distal hereditary motor, type 5C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Neuronopathy, distal hereditary motor, type 5A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

5.6

DANN

Uncertain

0.98

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.21

REVEL

Benign

0.20

Sift

Benign

0.19

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.14

ClinPred

0.0016

GERP RS

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over