rs786204416
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):βc.10466_10467delβ(p.Ser3489LeufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,609,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. S3489S) has been classified as Likely benign.
Frequency
Consequence
NM_014363.6 frameshift
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.10466_10467del | p.Ser3489LeufsTer2 | frameshift_variant | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.10466_10467del | p.Ser3489LeufsTer2 | frameshift_variant | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1457382Hom.: 0 AF XY: 0.00000414 AC XY: 3AN XY: 724686
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 16, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 06, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 18, 2021 | Variant summary: SACS c.10466_10467delCT (p.Ser3489LeufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245712 control chromosomes. c.10466_10467delCT has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and has been subsequently cited by others (example Desserre_2011, Criscuolo_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 13, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SACS protein in which other variant(s) (p.Asn4549Asp) have been determined to be pathogenic (PMID: 15156359, 21507954). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 188710). This premature translational stop signal has been observed in individual(s) with SACS-related conditions (PMID: 21597885). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser3489Leufs*2) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1091 amino acid(s) of the SACS protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at