rs778455259

chr11-62690820-C-Achr11-62690820-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001122955.4(BSCL2):c.1120G>T(p.Asp374Tyr) 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. 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. D374H) has been classified 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: 0.635

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2999407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSCL2	NM_001122955.4	c.1120G>T	p.Asp374Tyr	missense_variant	9/11	ENST00000360796.10
HNRNPUL2-BSCL2	NR_037946.1	n.3640G>T		non_coding_transcript_exon_variant	22/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSCL2	ENST00000360796.10	c.1120G>T	p.Asp374Tyr	missense_variant	9/11	1	NM_001122955.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Invitae

Apr 03, 2019

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 tolerated, but 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 disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 310 of the BSCL2 protein (p.Asp310Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Uncertain	0.98
Eigen	Benign	0.018
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.31	T;T;T;.;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	0.97	D;D;D;D;D;D;N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.012	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;T;T;T;T
Polyphen		0.31	.;.;.;B;B;B
Vest4		0.42, 0.43, 0.43
MutPred		0.33		.;.;.;Gain of phosphorylation at D310 (P = 0.0025);Gain of phosphorylation at D310 (P = 0.0025);Gain of phosphorylation at D310 (P = 0.0025);
MVP		0.91
ClinPred		0.95	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs778455259; hg19: chr11-62458292;