chr11-62692410-AG-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001122955.4(BSCL2):c.828del(p.Tyr277ThrfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,846 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: not found (cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
BSCL2
NM_001122955.4 frameshift
NM_001122955.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.231
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 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-62692410-AG-A is Pathogenic according to our data. Variant chr11-62692410-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 4540.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-62692410-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BSCL2 | NM_001122955.4 | c.828del | p.Tyr277ThrfsTer20 | frameshift_variant | 6/11 | ENST00000360796.10 | |
HNRNPUL2-BSCL2 | NR_037946.1 | n.3348del | non_coding_transcript_exon_variant | 19/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BSCL2 | ENST00000360796.10 | c.828del | p.Tyr277ThrfsTer20 | frameshift_variant | 6/11 | 1 | NM_001122955.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 31
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251342Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727218
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GnomAD4 genome Cov.: 31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 23, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Berardinelli–Seip congenital lipodystrophy (PMID: 11479539, 23659685). This variant is also known as c.980delC (p.F213fsX232) in the literature. ClinVar contains an entry for this variant (Variation ID: 4540). This variant is present in population databases (rs758843908, ExAC 0.01%). This sequence change creates a premature translational stop signal (p.Tyr213Thrfs*20) 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). - |
Congenital generalized lipodystrophy type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2001 | - - |
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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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at