rs780247476
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.10906C>T(p.Arg3636Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
SACS
NM_014363.6 stop_gained
NM_014363.6 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.72
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 18 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 139 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-23332970-G-A is Pathogenic according to our data. Variant chr13-23332970-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23332970-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.10906C>T | p.Arg3636Ter | stop_gained | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.10906C>T | p.Arg3636Ter | stop_gained | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250508Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135480
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461506Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 727052
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 07, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2020 | Variant summary: SACS c.10906C>T (p.Arg3636X) results in a premature termination codon in the last exon, that is not expected to result in nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.11374C>T (p.Arg3792X)). The variant allele was found at a frequency of 1.2e-05 in 250508 control chromosomes (gnomAD). The variant, c.10906C>T, has been reported in the literature in multiple compound heterozygous- and a homozygous individual affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (Vermeer_2008, Walsh_2017, Sun_2019, Tsugawa_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and laboratories classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 19, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 11, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 14, 2021 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | This sequence change creates a premature translational stop signal (p.Arg3636*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 944 amino acid(s) of the SACS protein. This variant is present in population databases (rs780247476, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with early-onset cerebellar ataxia (PMID: 18465152). ClinVar contains an entry for this variant (Variation ID: 212108). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2020 | The c.10906C>T (p.R3636*) alteration, located in exon 10 (coding exon 9) of the SACS gene, consists of a C to T substitution at nucleotide position 10906. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 3636. This alteration occurs at the 3' terminus of the SACS gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 20% of the protein. However, premature stop codons are typically deleterious in nature and a pathogenic truncating mutation downstream has been reported (Vermeer, 2008). This alteration was reported in two brothers and another unrelated patient with autosomal recessive spastic ataxia of Charlevoix Saguenay. They were all found to be compound heterozygous for a second truncating alteration in SACS (Vermeer, 2008; Sun, 2019). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
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