rs786205071
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001122955.4(BSCL2):c.517_518insA(p.Thr173AsnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
BSCL2
NM_001122955.4 frameshift
NM_001122955.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.94
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-62694680-G-GT is Pathogenic according to our data. Variant chr11-62694680-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 4536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BSCL2 | NM_001122955.4 | c.517_518insA | p.Thr173AsnfsTer5 | frameshift_variant | 4/11 | ENST00000360796.10 | |
HNRNPUL2-BSCL2 | NR_037946.1 | n.3037_3038insA | non_coding_transcript_exon_variant | 17/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BSCL2 | ENST00000360796.10 | c.517_518insA | p.Thr173AsnfsTer5 | frameshift_variant | 4/11 | 1 | NM_001122955.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135880
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727230
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital generalized lipodystrophy type 2 Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2004 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2023 | This variant is present in population databases (rs786205071, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr109Asnfs*5) in the BSCL2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BSCL2 are known to be pathogenic (PMID: 11479539, 23564749). This premature translational stop signal has been observed in individuals with autosomal recessive Berardinelli-Seip congenital lipodystrophy (PMID: 11479539, 17535271). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4536). This variant is also known as c.669insA . - |
Congenital generalized lipodystrophy type 2;C2931276:Hereditary spastic paraplegia 17;C4014700:Severe neurodegenerative syndrome with lipodystrophy;C5436838:Neuronopathy, distal hereditary motor, type 5C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
Berardinelli-Seip congenital lipodystrophy Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at