rs137852972

chr11-62702499-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001122955.4(BSCL2):c.455A>G(p.Asn152Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: BSCL2 NM_001122955.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1 O:1
• Conservation: PhyloP100: 6.41

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001122955.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-62702499-T-C is Pathogenic according to our data. Variant chr11-62702499-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62702499-T-C is described in Lovd as [Pathogenic]. Variant chr11-62702499-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSCL2	NM_001122955.4	c.455A>G	p.Asn152Ser	missense_variant	3/11	ENST00000360796.10
HNRNPUL2-BSCL2	NR_037946.1	n.2975A>G		non_coding_transcript_exon_variant	16/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSCL2	ENST00000360796.10	c.455A>G	p.Asn152Ser	missense_variant	3/11	1	NM_001122955.4	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251364 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135872

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460780 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2023	Published functional studies demonstrate protein over-expression and impairment of synaptic neurotransmission (Windpassinger et al., 2004; Wei et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17387721, 21750110, 22045697, 21957196, 18585921, 14981520, 18612770, 24345054, 16427281, 23553728, 19396477, 31589614, 31211173, 27549087, 29269637, 25219579, 27738760, 25454168, 20598714, 34085946, 32320108, 15732094) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	BSCL2: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary spastic paraplegia 17 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Spastic paraplegia 17, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PS4 => Prevalence in affecteds statistically increased over controls. N88S is the most frequent mutation. According to Ito & Suzuki 2009, 40 patients out of 48 patients from 16 families have N88S. In ExAC: 1 individual with N88S out of 60000 (PMID:18790819). PS3 => Well-established functional studies show a deleterious effect (PMID:17387721) (PMID:21750110). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -

Neuronopathy, distal hereditary motor, type 5C Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 17, 2022	- -

Neuronopathy, distal hereditary motor, type 5A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 09, 2018	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 19, 2016

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.263A>G (p.N88S) alteration is located in exon 3 (coding exon 2) of the BSCL2 gene. This alteration results from an A to G substitution at nucleotide position 263, causing the asparagine (N) at amino acid position 88 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the BSCL2 c.263A>G (p.N88S) alteration is classified as pathogenic for autosomal dominant BSCL2-related neurologic disorder; however, its clinical significance for autosomal recessive BSCL2-related syndrome is unclear. Based on data from gnomAD, the G allele has an overall frequency of 0.002% (4/251364) total alleles studied. The highest observed frequency was 0.01% (1/10074) of Ashkenazi Jewish alleles. This variant has been reported in multiple individuals with features of autosomal dominant BSCL2-related neurologic disorder and cosegregates with disease in multiple families (Thomas, 2022; Gentile, 2021; Fernández-Eulate, 2020; Minami, 2018; Musacchio, 2017; Ollivier, 2015; Monteiro, 2015; Rakoevi-Stojanovi, 2010; Brusse, 2009; Cafforio, 2008; van de Warrenburg, 2006; Auer-Grumbach, 2005; Windpassinger, 2004). This amino acid position is highly conserved in available vertebrate species. In vitro and in vivo functional studies demonstrate that this alteration disrupts the N-glycosylation site of seipin resulting in protein misfolding and accumulation consistent with a toxic gain-of-function effect (Lundin, 2006; Ito, 2007; Windpassinger, 2004; Ito, 2008; Fei, 2011; Yagi, 2011; Ito, 2012). Additional functional studies show aberrant neuronal electrophysiology and synaptic plasticity in vitro (Wei, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Peripheral neuropathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 88 of the BSCL2 protein (p.Asn88Ser). This variant is present in population databases (rs137852972, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant BSCL2-related conditions (PMID: 14981520, 15732094, 16427281, 20598714, 23553728, 25219579, 25454168). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4543). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BSCL2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BSCL2 function (PMID: 14981520, 17387721, 18585921, 21957196, 22045697, 24345054). For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 24, 2020

- -

Berardinelli-Seip congenital lipodystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jan 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D;D;.;.;D;D;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.089	T;T;T;D;D;D;T;T;T
Sift4G	Uncertain	0.019	D;D;D;D;D;D;.;.;.
Polyphen		0.94, 1.0	.;P;.;D;D;D;.;.;.
Vest4		0.91
MutPred		0.62		.;Gain of disorder (P = 0.0519);.;Gain of disorder (P = 0.0519);Gain of disorder (P = 0.0519);Gain of disorder (P = 0.0519);Gain of disorder (P = 0.0519);.;Gain of disorder (P = 0.0519);
MVP		0.95
ClinPred		0.69	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137852972; hg19: chr11-62469971;