GNB5

Chr 15AR

G protein subunit beta 5

Also known as: GB5, HG2E, IDDCA, LADCI, LDMLS1, LDMLS2, gbeta5

NCBI Gene: 10681 ENSG00000069966 UniProt: O14775 OMIM: 604447

The protein functions as a beta subunit of heterotrimeric G proteins that regulate signal transduction between cellular receptors and effector proteins. Biallelic mutations cause Lodder-Merla syndrome, an autosomal recessive disorder characterized by intellectual disability, developmental delay, and cardiac arrhythmias. The pathogenic mechanism involves dominant-negative effects of the mutant protein.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmiaMIM #617173

Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmiaMIM #617182

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia; Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.97

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — GNB5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.66

OE 0.63 (0.42–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.50Z-score

OE missense 0.72 (0.64–0.82)

167 obs / 231.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.42–0.97)

0≤0.351.4

Missense OE?0.72 (0.64–0.82)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 15 / 23.7Missense obs/exp: 167 / 231.4Syn Z: 0.13

Background carrier burden — how many people carry a rare variant somewhere in GNB5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

539 rare PASS variants

Rare truncating (LoF)

1 in 1,000

88 rare PASS variants

Rare synonymous (reference)

1 in 180

243 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GNB5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 1,500
South Asian	~43k	1 in 110	1 in 830
Remaining (unassigned)	~30k	1 in 130	1 in 1,600
European (Finnish)	~27k	1 in 730	1 in 3,300
Admixed American	~22k	1 in 130	1 in 1,100
African / African American	~21k	1 in 120	1 in 1,800
East Asian	~20k	1 in 130	1 in 1,400
Ashkenazi Jewish	~13k	1 in 780	none seen
Middle Eastern	~2,884	1 in 190	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 12 coding exons well covered in gnomAD exomes; exons 3, 6, 10, 11, 13 marginal. Genomes: all 12.? see exons ↓