SACS

sacsin molecular chaperone, the group of Protein phosphatase 1 regulatory subunits|DNAJ (HSP40) heat shock proteins

Basic information

Region (hg38): 13:23288689-23433763

Links

ENSG00000151835 ∙ NCBI:26278 ∙ OMIM:604490 ∙ HGNC:10519 ∙ Uniprot:Q9NZJ4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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
• Charlevoix-Saguenay spastic ataxia (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

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 ClinVar and linked to the SACS gene.

• Spastic paraplegia (238 variants)
• Charlevoix-Saguenay spastic ataxia (80 variants)
• not provided (33 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2C (17 variants)
• Hereditary spastic paraplegia (6 variants)
• Inborn genetic diseases (6 variants)
• Charcot-Marie-Tooth disease X-linked dominant 1 (1 variants)
• Abnormal central motor function (1 variants)
• Autosomal recessive spastic ataxia (1 variants)
• Ataxia, spastic, childhood-onset, autosomal recessive, with optic atrophy and intellectual disability (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.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			15	1572	19	1606
missense	10	24	529	474	75	1112
nonsense	101	135	4			240
start loss		2				2
frameshift	183	279	7			469
inframe indel			46			46
splice donor/acceptor (+/-2bp)		11	1			12
splice region	1		3	27	3	34
non coding	17	26	92	192	38	365
Total	311	477	694	2238	132

Highest pathogenic variant AF is 0.000158

Variants in SACS

This is a list of pathogenic ClinVar variants found in the SACS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
13-23295398-C-CT		Autosomal recessive limb-girdle muscular dystrophy type 2C	Benign (Nov 07, 2023)
13-23295400-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2C	Likely benign (Aug 11, 2023)
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 classifications of pathogenicity (Jan 28, 2024)
13-23295409-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2C	Likely benign (Oct 28, 2023)
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)
13-23295411-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2C	Likely benign (Nov 18, 2023)
13-23295416-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2C	Likely benign (Jan 03, 2024)
13-23295416-G-T		not specified • Autosomal recessive limb-girdle muscular dystrophy type 2C	Conflicting classifications of pathogenicity (Jan 22, 2024)
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 (Feb 05, 2024)
13-23295426-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2C	Uncertain significance (Jan 07, 2019)
13-23295428-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2C	Likely benign (Jan 11, 2024)
13-23295429-CT-C		Autosomal recessive limb-girdle muscular dystrophy type 2C • SGCG-related congenital myopathy • Autosomal recessive limb-girdle muscular dystrophy	Likely pathogenic (Jan 08, 2025)
13-23295431-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2C	Likely benign (Nov 13, 2023)
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)
13-23295435-GAACATTC-G		Autosomal recessive limb-girdle muscular dystrophy type 2C	Pathogenic (Jul 10, 2023)
13-23295438-C-A		Inborn genetic diseases	Uncertain significance (May 28, 2024)
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/Likely pathogenic (Mar 03, 2024)

GnomAD

Source: gnomAD

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: 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
• 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