rs770641122

Positions:

chr11-62705458-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The ENST00000360796.10(BSCL2):c.247G>A(p.Val83Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V83V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

BSCL2
ENST00000360796.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.184

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:):

HNRNPUL2-BSCL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a topological_domain Lumenal (size 194) in uniprot entity BSCL2_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) in ENST00000360796.10

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056014717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BSCL2	NM_001122955.4 linkuse as main transcript	c.247G>A	p.Val83Ile	missense_variant	2/11	ENST00000360796.10	NP_001116427.1
HNRNPUL2-BSCL2	NR_037946.1 linkuse as main transcript	n.2767G>A		non_coding_transcript_exon_variant	15/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BSCL2	ENST00000360796.10 linkuse as main transcript	c.247G>A	p.Val83Ile	missense_variant	2/11	1	NM_001122955.4	ENSP00000354032	A2	Q96G97-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251220

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2020

The p.V19I variant (also known as c.55G>A), located in coding exon 1 of the BSCL2 gene, results from a G to A substitution at nucleotide position 55. The valine at codon 19 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 19 of the BSCL2 protein (p.Val19Ile). This variant is present in population databases (rs770641122, gnomAD 0.002%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 29336362). ClinVar contains an entry for this variant (Variation ID: 476813). 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 not expected to disrupt BSCL2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

.;.;.;T;T;T;.;T;T;.;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.77

T;T;T;.;.;T;T;T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.056

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

.;N;.;N;N;N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.36

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.36

T;T;T;T;T;T;.;.;.;T;T

Polyphen

0.0010

.;B;.;B;B;B;.;.;.;.;.

Vest4

0.035

MutPred

0.45

.;Gain of catalytic residue at V19 (P = 0.0693);.;Gain of catalytic residue at V19 (P = 0.0693);Gain of catalytic residue at V19 (P = 0.0693);Gain of catalytic residue at V19 (P = 0.0693);Gain of catalytic residue at V19 (P = 0.0693);.;Gain of catalytic residue at V19 (P = 0.0693);.;.;

MVP

0.38

ClinPred

0.034

GERP RS

1.9

Varity_R

0.031

gMVP

0.20

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