chr11-62692797-C-A

Variant names:

• chr11-62692797-C-A
• rs987465261
• NM_001122955.4:c.631G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001122955.4(BSCL2):​c.631G>T​(p.Val211Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BSCL2 NM_001122955.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.43

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

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Lumenal (size 194) in uniprot entity BSCL2_HUMAN there are 20 pathogenic changes around while only 3 benign (87%) in NM_001122955.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BSCL2	NM_001122955.4	c.631G>T	p.Val211Leu	missense_variant, splice_region_variant	Exon 5 of 11	ENST00000360796.10	NP_001116427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BSCL2	ENST00000360796.10	c.631G>T	p.Val211Leu	missense_variant, splice_region_variant	Exon 5 of 11	1	NM_001122955.4	ENSP00000354032.5
HNRNPUL2-BSCL2	ENST00000403734.2	n.*682G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 24	2		ENSP00000456010.1
HNRNPUL2-BSCL2	ENST00000403734.2	n.*682G>T		3_prime_UTR_variant	Exon 18 of 24	2		ENSP00000456010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;.;.;D;D;D;.;T;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;.;.;D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.4	.;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.041	D;D;D;T;T;T;D;D;T
Sift4G	Benign	0.16	T;T;T;T;T;T;.;T;.
Polyphen		0.35, 0.67	.;B;.;P;P;P;.;.;.
Vest4		0.41
MutPred		0.50		.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;
MVP		0.88
ClinPred		0.81	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.14		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: rs987465261; hg19: chr11-62460269;