LMBRD2

Chr 5AD

LMBR1 domain containing 2

Also known as: DENBA

NCBI Gene: 92255 ENSG00000164187 UniProt: Q68DH5 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

Involved in adrenergic receptor signaling pathway. Located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.551 OMIM phenotype

Clinical Summary— LMBRD2

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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

10 unique Pathogenic / Likely Pathogenic· 113 VUS of 158 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 OE?0.35 (0.23–0.55)

0≤0.351.4

Missense OE?0.66 (0.60–0.74)

0≤0.61.4

Synonymous OE?0.90

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

This gene — mechanism propensity

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 · 100% of P/LP are missense

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.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 32820033 ↗

ClinVar Variant Classifications

158 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic10

VUS113

Likely Benign9

Benign5

Conflicting2

Likely Pathogenic

113

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	10	0	0	10
VUS	6	105	2	0	113
Likely Benign	0	7	1	1	9
Benign	0	1	1	3	5
Conflicting	—				2
Total	6	123	4	4	139

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap LMBRD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →