rs6856

chr11-62690803-T-Cchr11-62690803-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001122955.4(BSCL2):c.1137A>G(p.Glu379=) variant causes a synonymous 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. 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_001122955.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: -0.198

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:):

ACMG classification

Verdict is Benign. Variant got -21 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].
• BP7: Synonymous conserved (PhyloP=-0.198 with no splicing effect.
• 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	UniProt
BSCL2	NM_001122955.4	c.1137A>G	p.Glu379=	synonymous_variant	9/11	ENST00000360796.10
HNRNPUL2-BSCL2	NR_037946.1	n.3657A>G		non_coding_transcript_exon_variant	22/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSCL2	ENST00000360796.10	c.1137A>G	p.Glu379=	synonymous_variant	9/11	1	NM_001122955.4	A2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25255 AN: 152094 Hom.: 2289 Cov.: 33

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

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.: 35 AF XY: 0.209 AC XY: 152096 AN XY: 726820

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.: 33 AF XY: 0.162 AC XY: 12026 AN XY: 74430

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:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Congenital generalized lipodystrophy type 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

Invitae

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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. -

Neuronopathy, distal hereditary motor, type 5C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
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	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.20
Sift	Benign	0.19	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.14
ClinPred		0.0016	T
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

Other links and lift over

dbSNP: rs6856; hg19: chr11-62458275; COSMIC: COSV54017441; COSMIC: COSV54017441;