CASQ2

Chr 1AR

calsequestrin 2

Also known as: PDIB2

NCBI Gene: 845 ENSG00000118729 UniProt: O14958

The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Ventricular tachycardia, catecholaminergic polymorphic, 2MIM #611938

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

-0.2

Missense Z

1.38

LOEUF

Clinical Summary— CASQ2

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Gene-Disease Validity (ClinGen)

hypertrophic cardiomyopathy · ADDisputed

Disputed — evidence questions this relationship

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.38LOEUF

pLI 0.000

Z-score 0.26

OE 0.94 (0.65–1.38)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.20Z-score

OE missense 1.04 (0.93–1.16)

217 obs / 209.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.94 (0.65–1.38)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.93–1.16)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07

0≤1.21.6

LoF obs/exp: 19 / 20.3Missense obs/exp: 217 / 209.1Syn Z: -0.47

0.6647th %ile

GOF

0.4874th %ile

LOF

0.2970th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

CASQ2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CASQ2-related hypertrophic cardiomyopathy

disputed

ADUndeterminedUncertain

Cardiac

G2P ↗

CASQ2-related catecholaminergic polymorphic ventricular tachycardia

definitive

ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Cardiac

G2P ↗

splice region variantmissense variantstop gained NMD triggeringsplice donor variant NMD triggeringframeshift variant NMD triggeringsplice acceptor variant NMD triggering

CASQ2-related catecholaminergic polymorphic ventricular tachycardia

moderate

ADUndeterminedAltered Gene Product Structure, Decreased Gene Product Level

Cardiac

G2P ↗

splice region variantmissense variantstop gained NMD triggeringsplice donor variant NMD triggeringframeshift variant NMD triggeringsplice acceptor variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org