11-62690383-G-A

Position:

• chr11-62690383-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122955.4(BSCL2):​c.1373C>T​(p.Thr458Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BSCL2 NM_001122955.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25362438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BSCL2	NM_001122955.4	c.1373C>T	p.Thr458Ile	missense_variant	11/11	ENST00000360796.10	NP_001116427.1
HNRNPUL2-BSCL2	NR_037946.1	n.3893C>T		non_coding_transcript_exon_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BSCL2	ENST00000360796.10	c.1373C>T	p.Thr458Ile	missense_variant	11/11	1	NM_001122955.4	ENSP00000354032	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2019

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BSCL2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 394 of the BSCL2 protein (p.Thr394Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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	0.080
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	.;.;.;T;T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.75	T;T;T;T;.;.;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.97	.;.;.;.;L;L;L
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.8	D;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.088	T;T;T;D;T;T;T
Sift4G	Benign	0.29	T;T;T;.;T;T;T
Polyphen		0.0010	.;.;.;.;B;B;B
Vest4		0.18, 0.18, 0.10, 0.10, 0.096
MutPred		0.25		.;.;.;.;Loss of glycosylation at T394 (P = 0.004);Loss of glycosylation at T394 (P = 0.004);Loss of glycosylation at T394 (P = 0.004);
MVP		0.87
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.044
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1945272396; hg19: chr11-62457855;