rs145649423

Positions:

chr11-62690476-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000360796.10(BSCL2):c.1280T>C(p.Leu427Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,614,202 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L427L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 19 hom. )

Consequence

BSCL2
ENST00000360796.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:18O:1

Conservation

PhyloP100: 1.40

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006423205).

BP6

Variant 11-62690476-A-G is Benign according to our data. Variant chr11-62690476-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128532.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=10, Uncertain_risk_allele=1}. Variant chr11-62690476-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00295 (4313/1461876) while in subpopulation MID AF= 0.00936 (54/5768). AF 95% confidence interval is 0.00737. There are 19 homozygotes in gnomad4_exome. There are 2219 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BSCL2	NM_001122955.4 linkuse as main transcript	c.1280T>C	p.Leu427Pro	missense_variant	11/11	ENST00000360796.10	NP_001116427.1
HNRNPUL2-BSCL2	NR_037946.1 linkuse as main transcript	n.3800T>C		non_coding_transcript_exon_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BSCL2	ENST00000360796.10 linkuse as main transcript	c.1280T>C	p.Leu427Pro	missense_variant	11/11	1	NM_001122955.4	ENSP00000354032	A2	Q96G97-4

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

453

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00454

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00352

AC:

883

AN:

251144

Hom.:

AF XY:

0.00372

AC XY:

505

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00373

Gnomad ASJ exome

AF:

0.00646

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00295

AC:

4313

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

2219

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00373

Gnomad4 ASJ exome

AF:

0.00597

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.00133

Gnomad4 NFE exome

AF:

0.00313

Gnomad4 OTH exome

AF:

0.00334

GnomAD4 genome

AF:

0.00297

AC:

452

AN:

152326

Hom.:

Cov.:

AF XY:

0.00268

AC XY:

200

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00454

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00433

Hom.:

Bravo

AF:

0.00306

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00361

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:18Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:9

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	This variant is associated with the following publications: (PMID: 29482223, 33111339) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BSCL2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -

Congenital generalized lipodystrophy type 2

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain risk allele, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in BSCL2 gene are associated with Congenital generalized lipodystrophy, type 2, which can present with insulin resistance, fatty liver and diabetes.However, the role of this particular variant rs145649423 of Congenital Generalized Lipodystrophy type 2 remains uncertain -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2021

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Aug 10, 2018

ACMG criteria: BS1 (0.7% in gnomAD AJ population, 0.3% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (3 homozygotes in gnomAD ENF pop) [REVEL 0.257, PP3 (4 predictors), BP4 (6 predictors)= conflicting evidence, not using]= benign -

Congenital generalized lipodystrophy type 2;C2931276:Hereditary spastic paraplegia 17;C4014700:Severe neurodegenerative syndrome with lipodystrophy;C5436838:Neuronopathy, distal hereditary motor, type 5C

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

Neuronopathy, distal hereditary motor, type 5A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.15

.;.;.;T;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.59

T;T;T;.;.;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.0064

T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.1

.;.;.;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.2

D;N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.092

T;T;T;T;T;T

Sift4G

Benign

0.091

T;T;T;T;T;T

Polyphen

0.0010

.;.;.;B;B;B

Vest4

0.30, 0.31, 0.28, 0.28, 0.27

MVP

0.84

ClinPred

0.042

GERP RS

0.28

Varity_R

0.077

gMVP

0.25

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.

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