rs1057517659

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1PM2

The NM_001122955.4(BSCL2):​c.385delCinsGGA​(p.Pro129fs) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P129R?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

BSCL2
NM_001122955.4 frameshift, missense

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1O:1

Conservation

PhyloP100: 8.68
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PS1
Transcript NM_001122955.4 (BSCL2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BSCL2NM_001122955.4 linkuse as main transcriptc.385delCinsGGA p.Pro129fs frameshift_variant, missense_variant 2/11 ENST00000360796.10 NP_001116427.1 Q96G97-4A0A024R540

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BSCL2ENST00000360796.10 linkuse as main transcriptc.385delCinsGGA p.Pro129fs frameshift_variant, missense_variant 2/111 NM_001122955.4 ENSP00000354032.5 Q96G97-4
HNRNPUL2-BSCL2ENST00000403734.2 linkuse as main transcriptn.*436delCinsGGA non_coding_transcript_exon_variant 15/242 ENSP00000456010.1 H3BQZ7
HNRNPUL2-BSCL2ENST00000403734.2 linkuse as main transcriptn.*436delCinsGGA 3_prime_UTR_variant 15/242 ENSP00000456010.1 H3BQZ7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Berardinelli-Seip congenital lipodystrophy Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium Ii, University Of MiamiJan 06, 2016- -
Congenital generalized lipodystrophy type 2 Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057517659; hg19: chr11-62472792; API