CASQ2

calsequestrin 2, the group of Protein disulfide isomerases

Basic information

Region (hg38): 1:115698038-115837921

Links

ENSG00000118729 ∙ NCBI:845 ∙ OMIM:114251 ∙ HGNC:1513 ∙ Uniprot:O14958 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• catecholaminergic polymorphic ventricular tachycardia 2 (Strong), mode of inheritance: AR
• catecholaminergic polymorphic ventricular tachycardia 2 (Moderate), mode of inheritance: AR
• catecholaminergic polymorphic ventricular tachycardia (Supportive), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia 2 (Moderate), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia 2 (Definitive), mode of inheritance: AR
• catecholaminergic polymorphic ventricular tachycardia 2 (Strong), mode of inheritance: AR
• hypertrophic cardiomyopathy (Disputed Evidence), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Definitive), mode of inheritance: AR
• catecholaminergic polymorphic ventricular tachycardia (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ventricular tachycardia, catecholaminergic, polymorphic, 2	AR	Cardiovascular	Individuals may present with sudden cardiac death (eg, in the setting of exercise or excited states), and the overall mortality in untreated individuals is high early in life, such that surveillance and preventive measures/medical management, including ICD treatment, may be helpful to help decrease morbidity (however, storms of ventricular tachycardia have been described as being treated but not terminated through ICD shocks, and did not degenerate to ventricular fibrillation)	Cardiovascular	11401939; 16908766; 22481011; 22650415

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CASQ2 gene.

• Catecholaminergic polymorphic ventricular tachycardia 1 (21 variants)
• Catecholaminergic polymorphic ventricular tachycardia 2 (4 variants)
• Cardiovascular phenotype (3 variants)
• not provided (2 variants)
• Catecholaminergic polymorphic ventricular tachycardia 2;Catecholaminergic polymorphic ventricular tachycardia 1 (1 variants)
• Catecholaminergic polymorphic ventricular tachycardia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CASQ2 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	1	127		129
missense		5	207	5	2	219
nonsense	12	7	1			20
start loss	1	1				2
frameshift	10	5	1	1		17
inframe indel			11	1		12
splice donor/acceptor (+/-2bp)	4	14	1			19
splice region		1	14	35	8	58
non coding			17	128	35	180
Total	27	33	239	262	37

Highest pathogenic variant AF is 0.0000460

Variants in CASQ2

This is a list of pathogenic ClinVar variants found in the CASQ2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-115698060-A-G		Sacral defect with anterior meningocele • Neural tube defect	Uncertain significance (Jan 13, 2018)
1-115698066-A-G		Neural tube defect • Sacral defect with anterior meningocele	Uncertain significance (Jan 13, 2018)
1-115698100-A-G		Sacral defect with anterior meningocele • Catecholaminergic polymorphic ventricular tachycardia • Neural tube defect	Benign/Likely benign (Jan 12, 2018)
1-115698135-T-TC		Catecholaminergic polymorphic ventricular tachycardia • Neural tube defect • Caudal regression sequence	Likely benign (Jun 14, 2016)
1-115698173-C-A		Sacral defect with anterior meningocele • Neural tube defect	Conflicting classifications of pathogenicity (Nov 01, 2022)
1-115698216-A-G		Neural tube defect • Sacral defect with anterior meningocele	Uncertain significance (Jan 13, 2018)
1-115700034-T-C		Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Jan 13, 2018)
1-115700050-ATTAG-A		Catecholaminergic polymorphic ventricular tachycardia	Uncertain significance (Jun 14, 2016)
1-115700116-CAT-C		Neural tube defect • Catecholaminergic polymorphic ventricular tachycardia • Caudal regression sequence	Likely benign (Jun 14, 2016)
1-115700189-T-C		Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Jan 12, 2018)
1-115700218-T-C		Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Jan 13, 2018)
1-115700223-AT-A		Neural tube defect • Catecholaminergic polymorphic ventricular tachycardia • Caudal regression sequence	Likely benign (Jun 14, 2016)
1-115700223-A-AT		Catecholaminergic polymorphic ventricular tachycardia	Uncertain significance (Jun 14, 2016)
1-115700312-G-A		Catecholaminergic polymorphic ventricular tachycardia 2 • Catecholaminergic polymorphic ventricular tachycardia 1;Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Apr 11, 2023)
1-115700586-G-A		Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Jan 13, 2018)
1-115700605-C-G		Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Jan 12, 2018)
1-115700609-C-G		Catecholaminergic polymorphic ventricular tachycardia • Neural tube defect • Catecholaminergic polymorphic ventricular tachycardia 2 • Caudal regression sequence	Benign/Likely benign (Jan 12, 2018)
1-115700667-A-G		Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Jan 13, 2018)
1-115700738-C-T		Catecholaminergic polymorphic ventricular tachycardia • Catecholaminergic polymorphic ventricular tachycardia 2 • Catecholaminergic polymorphic ventricular tachycardia 1;Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Apr 11, 2023)
1-115700759-G-A		Catecholaminergic polymorphic ventricular tachycardia • Neural tube defect • Catecholaminergic polymorphic ventricular tachycardia 2 • Caudal regression sequence	Benign/Likely benign (Jan 13, 2018)
1-115700784-G-A		Catecholaminergic polymorphic ventricular tachycardia 2 • Catecholaminergic polymorphic ventricular tachycardia 1;Catecholaminergic polymorphic ventricular tachycardia 2	Uncertain significance (Apr 11, 2023)
1-115700909-T-A		Catecholaminergic polymorphic ventricular tachycardia 2 • Catecholaminergic polymorphic ventricular tachycardia 2;Catecholaminergic polymorphic ventricular tachycardia 1	Uncertain significance (Apr 11, 2023)
1-115701066-A-C		Catecholaminergic polymorphic ventricular tachycardia 2	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-115701098-C-T		Neural tube defect • Catecholaminergic polymorphic ventricular tachycardia 2 • Caudal regression sequence	Benign/Likely benign (Apr 27, 2017)
1-115701103-A-G		Neural tube defect • Catecholaminergic polymorphic ventricular tachycardia • Catecholaminergic polymorphic ventricular tachycardia 2 • Caudal regression sequence	Benign/Likely benign (Apr 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CASQ2	protein_coding	protein_coding	ENST00000261448	11	68775

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.39e-12	0.0512	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.195	217	209	1.04	0.0000114	2701
Missense in Polyphen		71	78.289	0.9069		1033
Synonymous	-0.470	83	77.7	1.07	0.00000455	672
Loss of Function	0.262	19	20.3	0.937	9.67e-7	259

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000330	0.000329
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000176	0.000176
Middle Eastern	0.000163	0.000163
South Asian	0.000360	0.000359
Other	0.00	0.00

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. Calcium ions are bound by clusters of acidic residues at the protein surface, especially at the interface between subunits. Can bind around 60 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR2; this plays an important role in triggering muscle contraction. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats. {ECO:0000269|PubMed:16908766, ECO:0000269|PubMed:17881003, ECO:0000269|PubMed:18399795, ECO:0000269|PubMed:21416293}.
• Disease: DISEASE: Ventricular tachycardia, catecholaminergic polymorphic, 2 (CPVT2) [MIM:611938]: An arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. CPVT2 inheritance is autosomal recessive. {ECO:0000269|PubMed:11704930, ECO:0000269|PubMed:15485681, ECO:0000269|PubMed:16908766, ECO:0000269|PubMed:17881003, ECO:0000269|PubMed:18399795, ECO:0000269|PubMed:27157848}. 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: 0.153

Intolerance Scores

• loftool: 0.765
• rvis_EVS: -0.16
• rvis_percentile_EVS: 42.06

Haploinsufficiency Scores

• pHI: 0.121
• hipred: N
• hipred_score: 0.352
• ghis: 0.458

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.354

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Casq2
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype; homeostasis/metabolism phenotype; muscle phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; embryo phenotype; immune system phenotype; vision/eye phenotype

Gene ontology

• Biological process: regulation of heart rate;detection of calcium ion;striated muscle contraction;regulation of cell communication by electrical coupling;regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion;ion transmembrane transport;negative regulation of potassium ion transport;sarcomere organization;sequestering of calcium ion;protein polymerization;cardiac muscle contraction;regulation of membrane repolarization;negative regulation of ryanodine-sensitive calcium-release channel activity;cellular response to caffeine;Purkinje myocyte to ventricular cardiac muscle cell signaling;negative regulation of potassium ion transmembrane transporter activity;regulation of cardiac conduction
• Cellular component: cytoplasm;junctional sarcoplasmic reticulum membrane;sarcoplasmic reticulum;Z disc;junctional membrane complex;sarcoplasmic reticulum membrane;sarcoplasmic reticulum lumen;calcium channel complex
• Molecular function: calcium ion binding;protein binding;protein homodimerization activity;calcium-dependent protein binding