NM_001122955.4:c.478C>A

Variant names:

• chr11-62702476-G-T
• rs772536764
• NM_001122955.4:c.478C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_001122955.4(BSCL2):​c.478C>A​(p.Arg160Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,459,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BSCL2 NM_001122955.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 4.75
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001122955.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

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.478C>A	p.Arg160Ser	missense	Exon 3 of 11	NP_001116427.1	Q96G97-4
	BSCL2	NM_001386027.1		c.478C>A	p.Arg160Ser	missense	Exon 4 of 12	NP_001372956.1	J3KQ12
	BSCL2	NM_001386028.1		c.478C>A	p.Arg160Ser	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.478C>A	p.Arg160Ser	missense	Exon 3 of 11	ENSP00000354032.5	Q96G97-4
	BSCL2	ENST00000405837.5	TSL:1	c.478C>A	p.Arg160Ser	missense	Exon 4 of 12	ENSP00000385332.1	J3KQ12
	BSCL2	ENST00000407022.7	TSL:1	c.286C>A	p.Arg96Ser	missense	Exon 3 of 11	ENSP00000384080.3	Q96G97-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251270 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459764 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726276

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1110466

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Berardinelli-Seip congenital lipodystrophy (1)
1	-	-	Charcot-Marie-Tooth disease (1)
-	1	-	Charcot-Marie-Tooth disease type 2 (1)
-	1	-	Neuronopathy, distal hereditary motor, type 5C (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.65		Gain of ubiquitination at K93 (P = 0.0359)
MVP		0.92
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.83
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772536764; hg19: chr11-62469948;