rs876657720
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_014363.6(SACS):c.7641_7642insA(p.Glu2548ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K2547K) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
SACS
NM_014363.6 frameshift
NM_014363.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.69
Genes affected
SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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. There are 241 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-23336234-C-CT is Pathogenic according to our data. Variant chr13-23336234-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 228393.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.7641_7642insA | p.Glu2548ArgfsTer7 | frameshift_variant | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.7641_7642insA | p.Glu2548ArgfsTer7 | frameshift_variant | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive spastic ataxia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 08, 2015 | The p.Glu2548fs variant in SACS has not been previously reported in individuals with clinical features of autosomal recessive spastic ataxia of Charlevoix-Sague nay (ARSACS) or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positi on 2548 and leads to a premature termination codon 7 amino acids downstream. Thi s premature termination codon occurs within the last exon of the gene (exon 10), and is more likely to escape nonsense mediated decay (NMD). Therefore, this var iant is predicted to result in a truncated protein that is 2025 amino acids shor ter and lacks several functional domains of the normal protein. Loss of function variants in the SACS gene, most of which occur in exon 10, have been reported i n several patients with ARSACS (Bouhlal 2011), and animal models support a loss of function mechanism of disease (Lariviere 2015). In summary, this variant meet s our criteria to be classified as pathogenic for ARSACS in an autosomal recessi ve manner (http://www.partners.org/personalizedmedicine/LMM). - |
Computational scores
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Splicing
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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