chr11-62702499-T-C

Variant names:

• chr11-62702499-T-C
• rs137852972
• NM_001122955.4:c.455A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N152N) has been classified as Likely benign.

• 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:23 U:1 O:1
• Conservation: PhyloP100: 6.41
• Publications: 83 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_001122955.4
• PP5: Variant 11-62702499-T-C is Pathogenic according to our data. Variant chr11-62702499-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4543.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	c.455A>G	p.Asn152Ser	missense_variant	Exon 3 of 11	ENST00000360796.10	NP_001116427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BSCL2	ENST00000360796.10	c.455A>G	p.Asn152Ser	missense_variant	Exon 3 of 11	1	NM_001122955.4	ENSP00000354032.5
HNRNPUL2-BSCL2	ENST00000403734.2	n.*506A>G		non_coding_transcript_exon_variant	Exon 16 of 24	2		ENSP00000456010.1
HNRNPUL2-BSCL2	ENST00000403734.2	n.*506A>G		3_prime_UTR_variant	Exon 16 of 24	2		ENSP00000456010.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251364 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111266

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000501 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BSCL2: PP1:Strong, PS4, PM2, PM5:Supporting, PS3:Supporting -

Aug 17, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 17 Pathogenic:5 Other:1

Jun 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 16, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21750110, 24345054). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.66 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.82 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004543 /PMID: 14981520 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 14981520, 15732094, 23553728, 25219579). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 14981520, 15732094, 16427281). A different missense change at the same codon (p.Asn152Thr) has been reported to be associated with BSCL2 related disorder (PMID: 32108980). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

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Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Jun 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 30, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Northcott Neuroscience Laboratory, ANZAC Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 09, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Sep 19, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 17;C5436838:Neuronopathy, distal hereditary motor, type 5C Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP1_Strong+PP4+PS3_Supporting -

Inborn genetic diseases Pathogenic:1

Jun 06, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Sep 24, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;.;D;D;D;.;D;D
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
MutationAssessor	Uncertain	2.2	.;M;.;M;M;M;.;.;.
PhyloP100		6.4
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
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs137852972; hg19: chr11-62469971;