13-23340547-A-AT
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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):βc.3328_3329insAβ(p.Ile1110AsnfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000105 in 1,611,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.000011 ( 0 hom. )
Consequence
SACS
NM_014363.6 frameshift
NM_014363.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.96
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 431 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-23340547-A-AT is Pathogenic according to our data. Variant chr13-23340547-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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SACS | NM_014363.6 | c.3328_3329insA | p.Ile1110AsnfsTer2 | frameshift_variant | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.3328_3329insA | p.Ile1110AsnfsTer2 | frameshift_variant | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1459636Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9AN XY: 726100
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74246
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 27, 2015 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2003 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 03, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189157). This variant is also known as 1155insA. This premature translational stop signal has been observed in individual(s) with autosomal recessive cerebellar ataxia (PMID: 12873855). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ile1110Asnfs*2) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3470 amino acid(s) of the SACS protein. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at