rs786204628
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.12851_12854delAGAG(p.Glu4284AlafsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_014363.6 frameshift
Scores
Clinical Significance
Conservation
Publications
- Charlevoix-Saguenay spastic ataxiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.00000797 AC: 2AN: 251052 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461822Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727224 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:3
The frameshift variant c.12851_12854del (p.Glu4284AlafsTer23) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu4284AlafsTer23 variant is reported with the allele frequency of 0.0007966% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 4284, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.Glu4284AlafsTer23. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely pathogenic. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
- -
Spastic paraplegia Pathogenic:1
This sequence change creates a premature translational stop signal (p.Glu4284Alafs*23) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 296 amino acid(s) of the SACS protein. 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.Ser4496*) have been determined to be pathogenic (PMID: 15156359, 21507954; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant is also known as c.12846_12850delAGAG. This premature translational stop signal has been observed in individual(s) with clinical features of SACS-related conditions (PMID: 19529988, 30460542). This variant is present in population databases (rs786204628, gnomAD 0.002%). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at