rs137852972

Variant names:

• chr11-62702499-T-C
• rs137852972
• NM_001122955.4:c.455A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-62702499-T-C
• chr11-62702499-T-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_001122955.4(BSCL2):​c.455A>G​(p.Asn152Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N152N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: BSCL2 NM_001122955.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 U:1 O:1
• Conservation: PhyloP100: 6.41
• Publications: 83 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_001122955.4
• PP5: Variant 11-62702499-T-C is Pathogenic according to our data. Variant chr11-62702499-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.455A>G	p.Asn152Ser	missense	Exon 3 of 11	NP_001116427.1	Q96G97-4
	BSCL2	NM_001386027.1		c.455A>G	p.Asn152Ser	missense	Exon 4 of 12	NP_001372956.1	J3KQ12
	BSCL2	NM_001386028.1		c.455A>G	p.Asn152Ser	missense	Exon 4 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.455A>G	p.Asn152Ser	missense	Exon 3 of 11	ENSP00000354032.5	Q96G97-4
	BSCL2	ENST00000405837.5	TSL:1	c.455A>G	p.Asn152Ser	missense	Exon 4 of 12	ENSP00000385332.1	J3KQ12
	BSCL2	ENST00000407022.7	TSL:1	c.263A>G	p.Asn88Ser	missense	Exon 3 of 11	ENSP00000384080.3	Q96G97-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251364 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460780 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726720

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111266

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000501 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
5	-	-	Hereditary spastic paraplegia 17 (6)
3	-	-	Neuronopathy, distal hereditary motor, type 5C (3)
2	-	-	Neuronopathy, distal hereditary motor, type 5A (2)
-	1	-	Berardinelli-Seip congenital lipodystrophy (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Hereditary spastic paraplegia 17;C5436838:Neuronopathy, distal hereditary motor, type 5C (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not specified (1)
1	-	-	Peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.66
Sift	Benign	0.089	T
Sift4G	Uncertain	0.019	D
Polyphen		0.94	P
Vest4		0.91
MutPred		0.62		Gain of disorder (P = 0.0519)
MVP		0.95
ClinPred		0.69	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.78
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.060		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: rs137852972; hg19: chr11-62469971;