11-62702476-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001122955.4(BSCL2):c.478C>A(p.Arg160Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,459,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BSCL2 NM_001122955.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 4.75

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001122955.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSCL2	NM_001122955.4	c.478C>A	p.Arg160Ser	missense_variant	3/11	ENST00000360796.10
HNRNPUL2-BSCL2	NR_037946.1	n.2998C>A		non_coding_transcript_exon_variant	16/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSCL2	ENST00000360796.10	c.478C>A	p.Arg160Ser	missense_variant	3/11	1	NM_001122955.4	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251270 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135826

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459764 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726276

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Inherited Neuropathy Consortium

-

- -

Berardinelli-Seip congenital lipodystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Sep 28, 2017

- -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 641509). This variant has not been reported in the literature in individuals affected with BSCL2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 96 of the BSCL2 protein (p.Arg96Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.029	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;.;.;.
Polyphen		0.99, 1.0	.;D;.;D;D;D;.;.;.
Vest4		0.76
MutPred		0.65		.;Gain of ubiquitination at K93 (P = 0.0359);.;Gain of ubiquitination at K93 (P = 0.0359);Gain of ubiquitination at K93 (P = 0.0359);Gain of ubiquitination at K93 (P = 0.0359);Gain of ubiquitination at K93 (P = 0.0359);.;Gain of ubiquitination at K93 (P = 0.0359);
MVP		0.92
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772536764; hg19: chr11-62469948;