13-23338724-ATTTT-ATTTTT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.5151dupA(p.Ser1718IlefsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,605,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K1717K) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
SACS
NM_014363.6 frameshift
NM_014363.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0670
Publications
2 publications found
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]
SACS Gene-Disease associations (from GenCC):
- 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
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 555 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-23338724-A-AT is Pathogenic according to our data. Variant chr13-23338724-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 448205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_014363.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SACS | NM_014363.6 | MANE Select | c.5151dupA | p.Ser1718IlefsTer20 | frameshift | Exon 10 of 10 | NP_055178.3 | ||
| SACS | NM_001437336.1 | c.5178dupA | p.Ser1727IlefsTer20 | frameshift | Exon 11 of 11 | NP_001424265.1 | |||
| SACS | NM_001278055.2 | c.4710dupA | p.Ser1571IlefsTer20 | frameshift | Exon 8 of 8 | NP_001264984.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SACS | ENST00000382292.9 | TSL:5 MANE Select | c.5151dupA | p.Ser1718IlefsTer20 | frameshift | Exon 10 of 10 | ENSP00000371729.3 | ||
| SACS | ENST00000455470.6 | TSL:1 | c.2431+2720dupA | intron | N/A | ENSP00000406565.2 | |||
| SACS | ENST00000682944.1 | c.5178dupA | p.Ser1727IlefsTer20 | frameshift | Exon 11 of 11 | ENSP00000507173.1 |
Frequencies
GnomAD3 genomes 0.0000198 AC: 3AN: 151748Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
3
AN:
151748
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
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Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000599 AC: 14AN: 233762 AF XY: 0.0000553 show subpopulations
GnomAD2 exomes
AF:
AC:
14
AN:
233762
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1454044Hom.: 0 Cov.: 36 AF XY: 0.0000166 AC XY: 12AN XY: 722930 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
22
AN:
1454044
Hom.:
Cov.:
36
AF XY:
AC XY:
12
AN XY:
722930
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
32906
American (AMR)
AF:
AC:
2
AN:
43476
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
25810
East Asian (EAS)
AF:
AC:
0
AN:
39620
South Asian (SAS)
AF:
AC:
5
AN:
84772
European-Finnish (FIN)
AF:
AC:
0
AN:
53060
Middle Eastern (MID)
AF:
AC:
0
AN:
5718
European-Non Finnish (NFE)
AF:
AC:
12
AN:
1108678
Other (OTH)
AF:
AC:
1
AN:
60004
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000163534), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.330
Heterozygous variant carriers
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5
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10
13
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0.20
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0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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Age
GnomAD4 genome 0.0000198 AC: 3AN: 151748Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74094 show subpopulations
GnomAD4 genome
AF:
AC:
3
AN:
151748
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74094
show subpopulations
African (AFR)
AF:
AC:
3
AN:
41318
American (AMR)
AF:
AC:
0
AN:
15232
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3466
East Asian (EAS)
AF:
AC:
0
AN:
5176
South Asian (SAS)
AF:
AC:
0
AN:
4790
European-Finnish (FIN)
AF:
AC:
0
AN:
10558
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67902
Other (OTH)
AF:
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
2
AN:
3478
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
7
-
-
Charlevoix-Saguenay spastic ataxia (7)
2
-
-
not provided (2)
1
-
-
Hereditary spastic paraplegia (1)
1
-
-
Inborn genetic diseases (1)
1
-
-
Spastic paraplegia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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