SACS
sacsin molecular chaperone, the group of Protein phosphatase 1 regulatory subunits|DNAJ (HSP40) heat shock proteins
Basic information
Region (hg38): 13:23288688-23433763
Links
Phenotypes
GenCC
Source:
- Charlevoix-Saguenay spastic ataxia (Definitive), mode of inheritance: AR
- Charlevoix-Saguenay spastic ataxia (Strong), mode of inheritance: AR
- Charlevoix-Saguenay spastic ataxia (Definitive), mode of inheritance: AR
- Charlevoix-Saguenay spastic ataxia (Supportive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Spastic ataxia, Charlevoix-Saguenay type | AR | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Musculoskeletal; Neurologic; Ophthalmologic | 10655055; 12873855; 14718706; 14718708; 15985586; 18398442; 20876471; 21745802; 21993619; 22209141; 22892508; 27133561 |
ClinVar
This is a list of variants' phenotypes submitted to
- Spastic paraplegia (2516 variants)
- Charlevoix-Saguenay spastic ataxia (1039 variants)
- not provided (620 variants)
- Autosomal recessive limb-girdle muscular dystrophy type 2C (162 variants)
- Hereditary spastic paraplegia (155 variants)
- not specified (149 variants)
- Inborn genetic diseases (103 variants)
- Sarcoglycanopathy (25 variants)
- Limb-Girdle Muscular Dystrophy, Recessive (18 variants)
- Abnormal central motor function (3 variants)
- Autosomal recessive spastic ataxia (3 variants)
- - (3 variants)
- See cases (3 variants)
- Spastic ataxia (3 variants)
- Abnormality of brain morphology (2 variants)
- Autosomal recessive limb-girdle muscular dystrophy (1 variants)
- Charcot-Marie-Tooth disease X-linked dominant 1 (1 variants)
- Ataxia, spastic, childhood-onset, autosomal recessive, with optic atrophy and intellectual disability (1 variants)
- Hereditary ataxia (1 variants)
- Myoepithelial tumor (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the SACS gene is commonly pathogenic or not.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 22 | 1256 | 34 | 1312 | ||
| missense | 14 | 24 | 520 | 576 | 78 | 1212 |
| nonsense | 86 | 95 | 6 | 3 | 190 | |
| start loss | 0 | |||||
| frameshift | 110 | 123 | 50 | 283 | ||
| inframe indel | 41 | 54 | 95 | |||
| splice variant | 1 | 4 | 6 | 27 | 2 | 40 |
| non coding | 22 | 23 | 87 | 129 | 33 | 294 |
| Total | 274 | 323 | 691 | 1991 | 147 |
Highest pathogenic variant AF is 0.000158
Variants in SACS
This is a list of pathogenic ClinVar variants found in the SACS region.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 13-23295400-T-C | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Jul 12, 2022) | ||
| 13-23295405-T-A | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Mar 25, 2021) | ||
| 13-23295408-T-G | not specified • Autosomal recessive limb-girdle muscular dystrophy type 2C | Conflicting interpretations of pathogenicity (Nov 01, 2022) | ||
| 13-23295409-G-A | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Sep 15, 2021) | ||
| 13-23295409-G-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Mar 01, 2021) | ||
| 13-23295410-T-C | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Jul 13, 2022) | ||
| 13-23295416-G-A | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (May 07, 2022) | ||
| 13-23295416-G-T | not specified • Autosomal recessive limb-girdle muscular dystrophy type 2C | Conflicting interpretations of pathogenicity (Oct 31, 2022) | ||
| 13-23295419-T-C | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Jun 18, 2022) | ||
| 13-23295420-G-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic/Likely pathogenic (Jul 31, 2022) | ||
| 13-23295426-G-A | Autosomal recessive limb-girdle muscular dystrophy type 2C | Uncertain significance (Jan 07, 2019) | ||
| 13-23295429-CT-C | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic (Dec 16, 2022) | ||
| 13-23295431-T-C | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Sep 06, 2022) | ||
| 13-23295432-TTTGA-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic (May 08, 2021) | ||
| 13-23295435-G-C | Uncertain significance (Jun 21, 2017) | |||
| 13-23295435-G-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic (Aug 13, 2019) | ||
| 13-23295438-C-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Uncertain significance (Feb 05, 2022) | ||
| 13-23295439-A-G | Uncertain significance (Jun 02, 2017) | |||
| 13-23295441-TC-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic (Nov 01, 2020) | ||
| 13-23295442-C-G | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic (Apr 14, 2022) | ||
| 13-23295444-G-A | Autosomal recessive limb-girdle muscular dystrophy type 2C • not specified | Uncertain significance (Nov 22, 2022) | ||
| 13-23295448-A-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Conflicting interpretations of pathogenicity (Nov 01, 2022) | ||
| 13-23295449-G-A | Autosomal recessive limb-girdle muscular dystrophy type 2C | Likely benign (Jun 29, 2022) | ||
| 13-23295456-C-T | Autosomal recessive limb-girdle muscular dystrophy type 2C | Uncertain significance (Jul 22, 2021) | ||
| 13-23295456-C-CT | Autosomal recessive limb-girdle muscular dystrophy type 2C | Pathogenic (May 29, 2022) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| SACS | protein_coding | protein_coding | ENST00000382298 | 9 | 104877 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.09e-23 | 1.00 | 125502 | 0 | 246 | 125748 | 0.000979 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.938 | 2132 | 2.26e+3 | 0.944 | 0.000115 | 30262 |
| Missense in Polyphen | 1102 | 1321.1 | 0.83413 | 17801 | ||
| Synonymous | -1.48 | 892 | 838 | 1.06 | 0.0000438 | 8723 |
| Loss of Function | 6.42 | 66 | 151 | 0.437 | 0.00000862 | 2132 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00192 | 0.00192 |
| Ashkenazi Jewish | 0.000713 | 0.000695 |
| East Asian | 0.00103 | 0.00103 |
| Finnish | 0.000371 | 0.000370 |
| European (Non-Finnish) | 0.00119 | 0.00119 |
| Middle Eastern | 0.00103 | 0.00103 |
| South Asian | 0.000891 | 0.000882 |
| Other | 0.000502 | 0.000489 |
dbNSFP
Source:
- Function
- FUNCTION: Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins. {ECO:0000269|PubMed:19208651}.;
- Disease
- DISEASE: Spastic ataxia Charlevoix-Saguenay type (SACS) [MIM:270550]: A neurodegenerative disease characterized by early- onset cerebellar ataxia, spasticity, retinal hypermyelination, pyramidal signs, and both axonal and demyelinating neuropathy with loss of sensory nerve conduction and reduced motor conduction velocities. Other features include dysarthria, distal muscle wasting, nystagmus, defect in conjugate pursuit ocular movements, retinal striation (from prominent retinal nerves) obscuring the retinal blood vessels in places, and the frequent presence of mitral valve prolapse. {ECO:0000269|PubMed:10655055, ECO:0000269|PubMed:12873855, ECO:0000269|PubMed:14718708, ECO:0000269|PubMed:15156359, ECO:0000269|PubMed:15985586, ECO:0000269|PubMed:16007637, ECO:0000269|PubMed:17290461, ECO:0000269|PubMed:17716690, ECO:0000269|PubMed:18398442, ECO:0000269|PubMed:18465152, ECO:0000269|PubMed:18484239, ECO:0000269|PubMed:19529988, ECO:0000269|PubMed:20876471, ECO:0000269|PubMed:27133561}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.309
Intolerance Scores
- loftool
- 0.0165
- rvis_EVS
- -1.83
- rvis_percentile_EVS
- 2.1
Haploinsufficiency Scores
- pHI
- 0.665
- hipred
- N
- hipred_score
- 0.427
- ghis
- 0.529
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- gene_indispensability_pred
- N
- gene_indispensability_score
- 0.192
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |
Mouse Genome Informatics
- Gene name
- Sacs
- Phenotype
- cellular phenotype; muscle phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);
Gene ontology
- Biological process
- protein folding;negative regulation of inclusion body assembly
- Cellular component
- nucleus;cytoplasm;mitochondrion;axon;dendrite;cell body fiber
- Molecular function
- Hsp70 protein binding;chaperone binding;proteasome binding