NCALD

Chr 8

neurocalcin delta

NCBI Gene: 83988 ENSG00000104490 UniProt: P61601 OMIM: 606722

This gene encodes neurocalcin delta, a neuronal calcium sensor protein that binds calcium ions and regulates G protein-coupled receptor signaling, including calcium-dependent regulation of rhodopsin phosphorylation. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and seizures. The gene is highly constrained against loss-of-function variants (pLI 0.89, LOEUF 0.41), indicating that complete protein loss is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the neuronal calcium sensor (NCS) family of calcium-binding proteins. The protein contains an N-terminal myristoylation signal and four EF-hand calcium binding loops. The protein is cytosolic at resting calcium levels; however, elevated intracellular calcium levels induce a conformational change that exposes the myristoyl group, resulting in protein association with membranes and partial co-localization with the perinuclear trans-golgi network. The protein is thought to be a regulator of G protein-coupled receptor signal transduction. Several alternatively spliced variants of this gene have been determined, all of which encode the same protein; additional variants may exist but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.41

Clinical Summary— NCALD

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.893

Z-score 2.50

OE 0.00 (0.00–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.56Z-score

OE missense 0.60 (0.49–0.73)

70 obs / 117.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.41)

0≤0.351.4

Missense OE?0.60 (0.49–0.73)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 0 / 7.3Missense obs/exp: 70 / 117.6Syn Z: -0.15

This gene — mechanism propensity

0.7327th %ile

GOF

0.6832th %ile

LOF

0.3744th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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.