rs145766983
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.7273C>T(p.Arg2425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,212 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R2425R) 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.7273C>T | p.Arg2425Ter | stop_gained | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.7273C>T | p.Arg2425Ter | stop_gained | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151886Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249774Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135248
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461326Hom.: 0 Cov.: 37 AF XY: 0.0000151 AC XY: 11AN XY: 726928
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151886Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74144
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2022 | Variant summary: SACS c.7273C>T (p.Arg2425X) results in a premature termination codon, which are commonly known mechanisms for disease. While the variant is not predicted to lead to nonsense-mediated decay, it does disrupt the last 2155 amino acids of the protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 249774 control chromosomes. To our knowledge, no occurrence of c.7273C>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 20, 2022 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 04, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change creates a premature translational stop signal (p.Arg2425*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2155 amino acid(s) of the SACS protein. This variant is present in population databases (rs145766983, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 370415). This variant disrupts a region of the SACS protein in which other variant(s) (p.Ile2949Phefs*4) have been determined to be pathogenic (PMID: 23250129). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2018 | The R2425X variant in the SACS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. The R2425X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R2425X as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at