NECAB2

Chr 16

N-terminal EF-hand calcium binding protein 2

Also known as: EFCBP2, stip-2

NCBI Gene: 54550 ENSG00000103154 UniProt: Q7Z6G3 OMIM: 618130

The protein is a neuronal calcium-binding scaffold protein that modulates adenosine A2A and metabotropic glutamate receptor signaling and promotes ERK1/2 activation. Mutations cause neurodevelopmental disorders with intellectual disability, developmental delay, and seizures. Inheritance is autosomal dominant, and the gene shows minimal constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a neuronal calcium-binding protein that binds to and modulates the function of at least two receptors, adenosine A(2A) receptor and metabotropic glutamate receptor type 5. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.39

Clinical Summary— NECAB2

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Population Constraint (gnomAD)

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

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 176 VUS of 200 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.39LOEUF

pLI 0.000

Z-score 0.18

OE 0.96 (0.67–1.39)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-4.91Z-score

OE missense 1.99 (1.80–1.99)

390 obs / 196.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.96 (0.67–1.39)

0≤0.351.4

Missense OE?1.99 (1.80–1.99)

0≤0.61.4

Synonymous OE?1.98

0≤1.21.6

LoF obs/exp: 20 / 20.9Missense obs/exp: 390 / 196.3Syn Z: -6.92

This gene — mechanism propensity

0.6066th %ile

GOF

0.6930th %ile

LOF

0.4627th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS176

Likely Benign6

Benign1

Pathogenic

176

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	2	2
Likely Pathogenic	0	0	0	0
VUS	1	175	0	176
Likely Benign	0	6	0	6
Benign	0	0	1	1
Total	1	181	3	185

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

45 pathogenic / likely-pathogenic (of 81) ClinVar copy-number / structural variants overlap NECAB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →