LMBRD2

Chr 5AD

LMBR1 domain containing 2

Also known as: DENBA

NCBI Gene: 92255ENSG00000164187UniProt: Q68DH5OMIM: 619490

LMBRD2 encodes a membrane protein that negatively regulates beta-2 adrenergic receptor signaling and other G-protein coupled receptors by binding to ligand-activated receptors. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly. The gene shows tolerance to loss-of-function variation in the general population.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismADLOEUF 0.551 OMIM phenotype
Clinical Summary— LMBRD2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
6 unique Pathogenic / Likely Pathogenic· 68 VUS of 100 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.55LOEUF
pLI 0.000
Z-score 3.81
OE 0.35 (0.23–0.55)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.27Z-score
OE missense 0.66 (0.60–0.74)
241 obs / 362.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.35 (0.23–0.55)
0≤0.351.4
Missense OE0.66 (0.60–0.74)
0≤0.61.4
Synonymous OE0.90
0≤1.21.6
LoF obs/exp: 14 / 40.0Missense obs/exp: 241 / 362.8Syn Z: 0.85
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedLMBRD2-related intellectual disabilityOTHERAD
DN
0.6840th %ile
GOF
0.75top 25%
LOF
0.2872th %ile

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

GOFprediction above median · 1 literature citation
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.

Literature Evidence

GOFDe novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.PMID:32820033

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

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic6
VUS68
Likely Benign6
Conflicting1
6
Likely Pathogenic
68
VUS
6
Likely Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
5
1
0
6
VUS
2
64
2
0
68
Likely Benign
0
4
1
1
6
Benign
0
0
0
0
0
Conflicting
—1
Total2734181

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

View in ClinVar →

Protein Context — Lollipop Plot

LMBRD2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients