rs145649423

Variant names:

• chr11-62690476-A-G
• rs145649423
• NM_001122955.4:c.1280T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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:19 O:1
• Conservation: PhyloP100: 1.40
• Publications: 13 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 -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 VariationId is 128532.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 2219 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 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.1280T>C	p.Leu427Pro	missense	Exon 11 of 11	NP_001116427.1	Q96G97-4
	BSCL2	NM_001386027.1		c.1286T>C	p.Leu429Pro	missense	Exon 12 of 12	NP_001372956.1	J3KQ12
	BSCL2	NM_001386028.1		c.1280T>C	p.Leu427Pro	missense	Exon 12 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.1280T>C	p.Leu427Pro	missense	Exon 11 of 11	ENSP00000354032.5	Q96G97-4
	BSCL2	ENST00000405837.5	TSL:1	c.1286T>C	p.Leu429Pro	missense	Exon 12 of 12	ENSP00000385332.1	J3KQ12
	BSCL2	ENST00000407022.7	TSL:1	c.1088T>C	p.Leu363Pro	missense	Exon 11 of 11	ENSP00000384080.3	Q96G97-2

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

GnomAD2 exomes AF: 0.00352 AC: 883 AN: 251144 AF XY: 0.00372

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 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

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00373 AC: 167 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00597 AC: 156 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86258

European-Finnish (FIN) AF: 0.00133 AC: 71 AN: 53416

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00313 AC: 3478 AN: 1112002

Other (OTH) AF: 0.00334 AC: 202 AN: 60396

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00268 AC XY: 200 AN XY: 74498

African (AFR) AF: 0.000625 AC: 26 AN: 41586

American (AMR) AF: 0.00425 AC: 65 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00454 AC: 309 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00336 Hom.: 8

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	4	not specified (4)
-	1	1	Congenital generalized lipodystrophy type 2 (2)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Congenital generalized lipodystrophy type 2;C2931276:Hereditary spastic paraplegia 17;C4014700:Severe neurodegenerative syndrome with lipodystrophy;C5436838:Neuronopathy, distal hereditary motor, type 5C (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Neuronopathy, distal hereditary motor, type 5A (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.26
Sift	Benign	0.092	T
Sift4G	Benign	0.091	T
Polyphen		0.0010	B
Vest4		0.30
MVP		0.84
ClinPred		0.042	T
GERP RS		0.28
Varity_R		0.077
gMVP		0.25
Mutation Taster		=96/4	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: rs145649423; hg19: chr11-62457948; COSMIC: COSV106094993; COSMIC: COSV106094993;