rs281865118
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.7504C>T(p.Arg2502Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000103 in 1,461,782 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2502R) has been classified as Likely benign.
Frequency
Consequence
NM_014363.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.7504C>T | p.Arg2502Ter | stop_gained | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.7504C>T | p.Arg2502Ter | stop_gained | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251338Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135832
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461782Hom.: 0 Cov.: 37 AF XY: 0.00000963 AC XY: 7AN XY: 727188
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2023 | Variant summary: SACS c.7504C>T (p.Arg2502X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 2,078 amino acids of the protein. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251338 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7504C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (e.g., Engert_2000). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 10655055). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 03, 2015 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 10, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Oct 25, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Laboratory, Tarbiat Modares University | Mar 01, 2020 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg2502*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2078 amino acid(s) of the SACS protein. This variant is present in population databases (rs281865118, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 10655055, 30901567). This variant is also known as g.5254C>T. ClinVar contains an entry for this variant (Variation ID: 5513). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at