CASQ1

calsequestrin 1, the group of Protein disulfide isomerases

Basic information

Region (hg38): 1:160190575-160201886

Previous symbols: [ "CASQ" ]

Links

ENSG00000143318 ∙ NCBI:844 ∙ OMIM:114250 ∙ HGNC:1512 ∙ Uniprot:P31415 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tubular aggregate myopathy (Supportive), mode of inheritance: AD
• myopathy due to calsequestrin and SERCA1 protein overload (Supportive), mode of inheritance: AD
• myopathy due to calsequestrin and SERCA1 protein overload (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myopathy, vacuolar, with CASQ1 aggregates	AD	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	25116801

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CASQ1 gene.

• Myopathy due to calsequestrin and SERCA1 protein overload (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CASQ1 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			1	61	1	63
missense	1	1	117	2	4	125
nonsense			8			8
start loss			1	1		2
frameshift		1	6			7
inframe indel			5			5
splice donor/acceptor (+/-2bp)		1	8	1		10
splice region			11	9	2	22
non coding			5	33	7	45
Total	1	3	151	98	12

Variants in CASQ1

This is a list of pathogenic ClinVar variants found in the CASQ1 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-160190753-T-A			Likely benign (Nov 17, 2022)
1-160190754-G-A			Uncertain significance (Oct 05, 2022)
1-160190761-A-G			Uncertain significance (Feb 14, 2022)
1-160190766-C-G			Uncertain significance (Sep 01, 2022)
1-160190767-A-G			Uncertain significance (Feb 22, 2023)
1-160190768-G-A			Uncertain significance (Mar 10, 2023)
1-160190773-G-A			Uncertain significance (Aug 17, 2023)
1-160190777-C-A			Uncertain significance (Jul 25, 2022)
1-160190778-C-A		Inborn genetic diseases	Benign/Likely benign (Jan 29, 2024)
1-160190784-T-C			Likely benign (Sep 25, 2023)
1-160190789-C-T			Uncertain significance (Jan 18, 2024)
1-160190790-G-A		Inborn genetic diseases	Benign/Likely benign (Oct 15, 2022)
1-160190790-G-C			Likely benign (Aug 16, 2023)
1-160190796-GC-G		Myopathy due to calsequestrin and SERCA1 protein overload	Uncertain significance (Jun 10, 2021)
1-160190797-C-T		Inborn genetic diseases	Uncertain significance (Jun 05, 2023)
1-160190798-G-A			Uncertain significance (Jun 14, 2023)
1-160190799-G-C			Likely benign (Aug 03, 2023)
1-160190838-G-C			Uncertain significance (Jun 10, 2022)
1-160190840-C-A			Uncertain significance (Feb 03, 2022)
1-160190851-G-A			Uncertain significance (Nov 01, 2023)
1-160190854-C-A			Uncertain significance (Feb 23, 2023)
1-160190863-C-T			Likely benign (Jun 01, 2024)
1-160190864-TG-T			Uncertain significance (Jul 26, 2023)
1-160190869-T-C			Uncertain significance (Mar 07, 2020)
1-160190873-C-T			Uncertain significance (May 25, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CASQ1	protein_coding	protein_coding	ENST00000368078	11	11392

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.86e-18	0.00142	125440	2	306	125748	0.00123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0187	226	225	1.00	0.0000120	2640
Missense in Polyphen		64	71.781	0.8916		895
Synonymous	0.957	83	94.9	0.875	0.00000613	710
Loss of Function	-0.570	25	22.1	1.13	0.00000112	258

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000902	0.000901
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.00158	0.00158
Finnish	0.000786	0.000786
European (Non-Finnish)	0.00184	0.00183
Middle Eastern	0.00158	0.00158
South Asian	0.000822	0.000784
Other	0.00114	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle (PubMed:28895244). Calcium ions are bound by clusters of acidic residues at the protein surface, often at the interface between subunits. Can bind around 80 Ca(2+) ions (PubMed:28895244). Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction. Negatively regulates store-operated Ca(2+) entry (SOCE) activity (PubMed:27185316). {ECO:0000269|PubMed:22337878, ECO:0000269|PubMed:27185316, ECO:0000269|PubMed:28895244, ECO:0000303|PubMed:22337878}.
• Disease: DISEASE: Myopathy, vacuolar, with CASQ1 aggregates (VMCQA) [MIM:616231]: An autosomal dominant mild muscle disorder characterized by adult onset of muscle cramping and weakness as well as increased levels of serum creatine kinase. The disorder is not progressive, and some patients may be asymptomatic. {ECO:0000269|PubMed:25116801, ECO:0000269|PubMed:26136523, ECO:0000269|PubMed:27196359, ECO:0000269|PubMed:28895244}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, tubular aggregate, 1 (TAM1) [MIM:160565]: A rare congenital myopathy characterized by regular arrays of membrane tubules on muscle biopsies without additional histopathological hallmarks. Tubular aggregates in muscle are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They may occur in a variety of circumstances, including inherited myopathies, alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness. {ECO:0000269|PubMed:28895244}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Antiarrhythmic Pathway, Pharmacodynamics;Calcium Regulation in the Cardiac Cell (Consensus)

Recessive Scores

• pRec: 0.201

Intolerance Scores

• loftool: 0.733
• rvis_EVS: 0.6
• rvis_percentile_EVS: 82.74

Haploinsufficiency Scores

• pHI: 0.498
• hipred: N
• hipred_score: 0.167
• ghis: 0.422

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.598

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Casq1
• Phenotype: hematopoietic system phenotype; growth/size/body region phenotype; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: endoplasmic reticulum organization;skeletal muscle tissue development;response to heat;response to organic substance;regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion;response to denervation involved in regulation of muscle adaptation;ion transmembrane transport;sarcomere organization;protein polymerization;positive regulation of release of sequestered calcium ion into cytosol;positive regulation of store-operated calcium channel activity;regulation of cardiac conduction;regulation of store-operated calcium entry
• Cellular component: mitochondrion;mitochondrial matrix;endoplasmic reticulum;smooth endoplasmic reticulum;Golgi apparatus;terminal cisterna lumen;sarcoplasmic reticulum;Z disc;T-tubule;sarcoplasmic reticulum membrane;sarcoplasmic reticulum lumen
• Molecular function: calcium ion binding;protein binding;identical protein binding