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GeneBe

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

ENSG00000151835NCBI:26278OMIM:604490HGNC:10519Uniprot:Q9NZJ4AlphaFoldGenCCjaxSfariGnomADPubmed

Phenotypes

GenCC

Source: genCC

  • 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: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Spastic ataxia, Charlevoix-Saguenay typeARGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingMusculoskeletal; Neurologic; Ophthalmologic10655055; 12873855; 14718706; 14718708; 15985586; 18398442; 20876471; 21745802; 21993619; 22209141; 22892508; 27133561

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SACS gene.

  • 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)link
13-23295405-T-A Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Mar 25, 2021)link
13-23295408-T-G not specified • Autosomal recessive limb-girdle muscular dystrophy type 2C Conflicting interpretations of pathogenicity (Nov 01, 2022)link
13-23295409-G-A Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Sep 15, 2021)link
13-23295409-G-T Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Mar 01, 2021)link
13-23295410-T-C Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Jul 13, 2022)link
13-23295416-G-A Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (May 07, 2022)link
13-23295416-G-T not specified • Autosomal recessive limb-girdle muscular dystrophy type 2C Conflicting interpretations of pathogenicity (Oct 31, 2022)link
13-23295419-T-C Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Jun 18, 2022)link
13-23295420-G-T Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic/Likely pathogenic (Jul 31, 2022)link
13-23295426-G-A Autosomal recessive limb-girdle muscular dystrophy type 2C Uncertain significance (Jan 07, 2019)link
13-23295429-CT-C Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic (Dec 16, 2022)link
13-23295431-T-C Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Sep 06, 2022)link
13-23295432-TTTGA-T Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic (May 08, 2021)link
13-23295435-G-C Uncertain significance (Jun 21, 2017)link
13-23295435-G-T Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic (Aug 13, 2019)link
13-23295438-C-T Autosomal recessive limb-girdle muscular dystrophy type 2C Uncertain significance (Feb 05, 2022)link
13-23295439-A-G Uncertain significance (Jun 02, 2017)link
13-23295441-TC-T Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic (Nov 01, 2020)link
13-23295442-C-G Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic (Apr 14, 2022)link
13-23295444-G-A Autosomal recessive limb-girdle muscular dystrophy type 2C • not specified Uncertain significance (Nov 22, 2022)link
13-23295448-A-T Autosomal recessive limb-girdle muscular dystrophy type 2C Conflicting interpretations of pathogenicity (Nov 01, 2022)link
13-23295449-G-A Autosomal recessive limb-girdle muscular dystrophy type 2C Likely benign (Jun 29, 2022)link
13-23295456-C-T Autosomal recessive limb-girdle muscular dystrophy type 2C Uncertain significance (Jul 22, 2021)link
13-23295456-C-CT Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic (May 29, 2022)link

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SACSprotein_codingprotein_codingENST00000382298 9104877
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
1.09e-231.0012550202461257480.000979
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense0.93821322.26e+30.9440.00011530262
Missense in Polyphen11021321.10.8341317801
Synonymous-1.488928381.060.00004388723
Loss of Function6.42661510.4370.000008622132

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.001920.00192
Ashkenazi Jewish0.0007130.000695
East Asian0.001030.00103
Finnish0.0003710.000370
European (Non-Finnish)0.001190.00119
Middle Eastern0.001030.00103
South Asian0.0008910.000882
Other0.0005020.000489

dbNSFP

Source: dbNSFP

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

AllRecessiveDominant
MendelianHighMediumHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh

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