rs185341934

Variant names:

• chr11-62692394-G-A
• rs185341934
• NM_001122955.4:c.845C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_001122955.4(BSCL2):​c.845C>T​(p.Ala282Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,614,176 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A282T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: BSCL2 NM_001122955.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:12 O:1
• Conservation: PhyloP100: 8.36
• Publications: 6 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01549226).
• BP6: Variant 11-62692394-G-A is Benign according to our data. Variant chr11-62692394-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305177.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00111 (169/152316) while in subpopulation EAS AF = 0.00869 (45/5180). AF 95% confidence interval is 0.00667. There are 4 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BSCL2	NM_001122955.4	MANE Select	c.845C>T	p.Ala282Val	missense	Exon 6 of 11	NP_001116427.1	Q96G97-4
	BSCL2	NM_001386027.1		c.845C>T	p.Ala282Val	missense	Exon 7 of 12	NP_001372956.1	J3KQ12
	BSCL2	NM_001386028.1		c.845C>T	p.Ala282Val	missense	Exon 7 of 12	NP_001372957.1	Q96G97-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BSCL2	ENST00000360796.10	TSL:1 MANE Select	c.845C>T	p.Ala282Val	missense	Exon 6 of 11	ENSP00000354032.5	Q96G97-4
	BSCL2	ENST00000405837.5	TSL:1	c.845C>T	p.Ala282Val	missense	Exon 7 of 12	ENSP00000385332.1	J3KQ12
	BSCL2	ENST00000407022.7	TSL:1	c.653C>T	p.Ala218Val	missense	Exon 6 of 11	ENSP00000384080.3	Q96G97-2

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00181 AC: 455 AN: 251320 AF XY: 0.00135

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00905

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00652

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000542 AC: 792 AN: 1461860 Hom.: 7 Cov.: 32 AF XY: 0.000477 AC XY: 347 AN XY: 727232

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00948 AC: 424 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00617 AC: 245 AN: 39696

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112008

Other (OTH) AF: 0.00124 AC: 75 AN: 60396

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74482

African (AFR) AF: 0.000313 AC: 13 AN: 41570

American (AMR) AF: 0.00680 AC: 104 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00869 AC: 45 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.00207

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Congenital generalized lipodystrophy type 2 (2)
-	-	1	BSCL2-related disorder (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Neuronopathy, distal hereditary motor, type 5A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.95
ClinPred		0.083	T
GERP RS		4.6
PromoterAI		-0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.76
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs185341934; hg19: chr11-62459866; COSMIC: COSV54014862; COSMIC: COSV54014862;