chr11-62690369-AGGAACTAGAGCAGGTGGGGCGCTGTC-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_001122955.4(BSCL2):c.1361_1386del(p.Arg454LeufsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
BSCL2
NM_001122955.4 frameshift
NM_001122955.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.89
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 Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0202 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-62690369-AGGAACTAGAGCAGGTGGGGCGCTGTC-A is Pathogenic according to our data. Variant chr11-62690369-AGGAACTAGAGCAGGTGGGGCGCTGTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 947075.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BSCL2 | NM_001122955.4 | c.1361_1386del | p.Arg454LeufsTer16 | frameshift_variant | 11/11 | ENST00000360796.10 | |
HNRNPUL2-BSCL2 | NR_037946.1 | n.3881_3906del | non_coding_transcript_exon_variant | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BSCL2 | ENST00000360796.10 | c.1361_1386del | p.Arg454LeufsTer16 | frameshift_variant | 11/11 | 1 | NM_001122955.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251424Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461756Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727190
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic: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 | Sep 25, 2023 | This sequence change results in a frameshift in the BSCL2 gene (p.Arg390Leufs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the BSCL2 protein and extend the protein by 6 additional amino acid residues. This variant is present in population databases (rs779154593, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BSCL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 947075). This variant disrupts a region of the BSCL2 protein in which other variant(s) (p.Gln391*) have been determined to be pathogenic (PMID: 19226263, 24024128). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at