rs145649423

chr11-62690476-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001122955.4(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 NM_001122955.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:17 O:1
• Conservation: PhyloP100: 1.40

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 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=9, 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 GnomAdExome at 3 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSCL2	ENST00000360796.10	c.1280T>C	p.Leu427Pro	missense_variant	11/11	1	NM_001122955.4	A2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152208 Hom.: 1 Cov.: 33

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.: 3 AF XY: 0.00372 AC XY: 505 AN XY: 135818

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.: 19 Cov.: 32 AF XY: 0.00305 AC XY: 2219 AN XY: 727238

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.: 1 Cov.: 33 AF XY: 0.00268 AC XY: 200 AN XY: 74498

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.: 3

Bravo AF: 0.00306

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:17 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BSCL2: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	This variant is associated with the following publications: (PMID: 29482223, 33111339) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:2

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

Congenital generalized lipodystrophy type 2 Benign:1 Other:1

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 -
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. -

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

Invitae

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

- -

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

- -

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 -

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	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Benign	0.95
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.59	T;T;T;.;.;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.0064	T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs145649423; hg19: chr11-62457948;