SACS

protein-coding

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

Gene summary

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]

MANE transcript

NM_014363.6

Inheritance

ClinVar variants

P:1080U:1148B:2581

Top phenotype

Spastic ataxia, Charlevoix-Saguenay type

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr13:23,288,689-23,433,763

External References & Databases

Ensembl (ENSG00000151835)

Transcript & Mutation Effects

hg38 • Region Span ~145.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charlevoix-Saguenay spastic ataxiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: G2P

Charlevoix-Saguenay spastic ataxiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: Orphanet

Charlevoix-Saguenay spastic ataxiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Charlevoix-Saguenay spastic ataxiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: Natera

Charlevoix-Saguenay spastic ataxiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: Myriad Women's Health

Charlevoix-Saguenay spastic ataxiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: PanelApp Australia

Charlevoix-Saguenay spastic ataxiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010041

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic ataxia, Charlevoix-Saguenay typeAR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: 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

Refs: 10655055; 12873855; 14718706; 14718708; 15985586; 18398442; 20876471; 21745802; 21993619; 22209141; 22892508; 27133561

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SACS variants in ClinVar

18 Conditions Cataloged

Spastic paraplegiaTotal: 3369

Charlevoix-Saguenay spastic ataxiaTotal: 1774

not providedTotal: 888

Inborn genetic diseasesTotal: 475

not specifiedTotal: 269

SACS-related disorderTotal: 236

Hereditary spastic paraplegiaTotal: 144

See casesTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014363.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			61 clinvar	1729 clinvar	27 clinvar	1817
missense	14 clinvar	56 clinvar	1072 clinvar	776 clinvar	49 clinvar	1967
nonsense	118 clinvar	193 clinvar	6 clinvar			317
start loss		2 clinvar				2
frameshift	230 clinvar	447 clinvar	8 clinvar			685
splice donor/acceptor (+/-2bp)		20 clinvar	1 clinvar			21
Total	362	718	1148	2505	76	4809

Highest pathogenic variant AF is 0.000109135646

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014363.6	RefSeq	NP_055178.3	9	MANE Select
ENST00000382292.9	Ensembl	ENSP00000371729.3	9	MANE Select
NM_001278055.2	RefSeq	NP_001264984.1	5	Standard
NM_001437336.1	RefSeq	NP_001424265.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein folding
negative regulation of inclusion body assembly

Molecular Function

Hsp70 protein binding
chaperone binding
proteasome binding

Cellular Component

nucleus
cytoplasm
mitochondrion
axon
dendrite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382298
Coding exons: 9
Length: 104877
Individuals with no LoFs: 125502
Homozygous LoFs: 0
Heterozygous LoFs: 246
Defined: 125748
p: 0.000979

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.938	2132	2.26e+3	0.944	0.000115	30262
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0010	notable
Latino/Admixed American	0.00087	0.00087	rare
Ashkenazi Jewish	0.00071	0.00069	rare
East Asian	0.0010	0.0010	notable
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.0012	0.0012	notable
South Asian	0.00089	0.00088	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.192

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High