NBEA

Chr 13AD

neurobeachin

Also known as: BCL8B, LYST2, NEDEGE

NCBI Gene: 26960 ENSG00000172915 UniProt: Q8NFP9 OMIM: 604889

This protein anchors protein kinase A to specific membrane locations and is involved in neuronal membrane trafficking. Mutations cause neurodevelopmental disorder with or without early-onset generalized epilepsy with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI = 1, LOEUF = 0.074), indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of a large, diverse group of A-kinase anchor proteins that target the activity of protein kinase A to specific subcellular sites by binding to its type II regulatory subunits. Brain-specific expression and coat protein-like membrane recruitment of a highly similar protein in mouse suggest an involvement in neuronal post-Golgi membrane traffic. Mutations in this gene may be associated with a form of autism. This gene and its expression are frequently disrupted in patients with multiple myeloma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants may exist, but their full-length nature has not been determined.[provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.071 OMIM phenotype

Clinical Summary— NBEA

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

92 unique Pathogenic / Likely Pathogenic· 624 VUS of 979 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 10.66

OE 0.04 (0.02–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.51Z-score

OE missense 0.60 (0.56–0.63)

875 obs / 1469.5 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.07)

0≤0.351.4

Missense OE?0.60 (0.56–0.63)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 5 / 142.1Missense obs/exp: 875 / 1469.5Syn Z: 0.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNBEA-related neurodevelopment disorder with seizuresLOFAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.4184th %ile

LOF

0.73top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 78% of P/LP variants are LoF · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFThese findings indicate that Nbea haploinsufficiency leads to various molecular and cellular changes that affect neuroplasticity and behavioral functions in mice, and could thus underlie the ASD symptomatology in NBEA deficient humans.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 23153818 ↗

ClinVar Variant Classifications

979 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42

Likely Pathogenic50

VUS624

Likely Benign195

Benign14

Conflicting20

Pathogenic

Likely Pathogenic

624

VUS

195

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	36	5	1	0	42
Likely Pathogenic	36	11	3	0	50
VUS	10	587	23	4	624
Likely Benign	1	69	16	109	195
Benign	0	4	4	6	14
Conflicting	—				20
Total	83	676	47	119	945

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap NBEA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →