rs772516974

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001122955.4(BSCL2):​c.1147G>A​(p.Gly383Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

BSCL2
NM_001122955.4 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.13
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11640918).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BSCL2NM_001122955.4 linkc.1147G>A p.Gly383Arg missense_variant Exon 9 of 11 ENST00000360796.10 NP_001116427.1 Q96G97-4A0A024R540

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BSCL2ENST00000360796.10 linkc.1147G>A p.Gly383Arg missense_variant Exon 9 of 11 1 NM_001122955.4 ENSP00000354032.5 Q96G97-4
HNRNPUL2-BSCL2ENST00000403734.2 linkn.*1198G>A non_coding_transcript_exon_variant Exon 22 of 24 2 ENSP00000456010.1 H3BQZ7
HNRNPUL2-BSCL2ENST00000403734.2 linkn.*1198G>A 3_prime_UTR_variant Exon 22 of 24 2 ENSP00000456010.1 H3BQZ7

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000448
AC:
11
AN:
245394
Hom.:
0
AF XY:
0.0000451
AC XY:
6
AN XY:
132996
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:
0.0000920
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000657
AC:
96
AN:
1461400
Hom.:
0
Cov.:
32
AF XY:
0.0000633
AC XY:
46
AN XY:
726960
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000189
Gnomad4 NFE exome
AF:
0.0000836
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000231
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.955G>A (p.G319R) alteration is located in exon 9 (coding exon 8) of the BSCL2 gene. This alteration results from a G to A substitution at nucleotide position 955, causing the glycine (G) at amino acid position 319 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2 Uncertain:1
Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 319 of the BSCL2 protein (p.Gly319Arg). This variant is present in population databases (rs772516974, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with BSCL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 476819). 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 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. -

Congenital generalized lipodystrophy type 2;C2931276:Hereditary spastic paraplegia 17;C4014700:Severe neurodegenerative syndrome with lipodystrophy;C5436838:Neuronopathy, distal hereditary motor, type 5C Uncertain:1
Feb 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Apr 01, 2019
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Benign
0.15
.;.;T;T;T
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.11
N
LIST_S2
Uncertain
0.88
D;D;.;.;D
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.12
T;T;T;T;T
MetaSVM
Benign
-0.47
T
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-2.1
N;N;N;N;N
REVEL
Benign
0.072
Sift
Benign
0.055
T;D;D;D;D
Sift4G
Uncertain
0.010
D;D;D;D;D
Polyphen
0.10
.;.;B;B;B
Vest4
0.22
MutPred
0.33
.;.;Loss of glycosylation at S318 (P = 0.0368);Loss of glycosylation at S318 (P = 0.0368);Loss of glycosylation at S318 (P = 0.0368);
MVP
0.77
ClinPred
0.081
T
GERP RS
1.3
Varity_R
0.073
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772516974; hg19: chr11-62458265; COSMIC: COSV54015834; COSMIC: COSV54015834; API