GNB2

Chr 7

G protein subunit beta 2

Also known as: HG2C1, NEDHYDF, SSS4, SSS4; NEDHYDF

NCBI Gene: 2783 ENSG00000172354 UniProt: P62879

The GNB2 protein functions as the beta subunit of heterotrimeric G proteins, regulating alpha subunit activity and mediating signal transduction between cell surface receptors and intracellular effector proteins. Mutations cause autosomal dominant neurodevelopmental disorder with hypotonia and dysmorphic facies, and potentially sick sinus syndrome, affecting both the nervous system and cardiac conduction. The gene is highly constrained against loss-of-function variants (pLI = 0.99), indicating that such mutations are likely to have severe consequences.

ResearchSummary from RefSeq, OMIM, UniProt

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. This gene contains a trinucleotide (CCG) repeat length polymorphism in its 5' UTR. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.27

Clinical Summary— GNB2

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 61 VUS of 109 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.27LOEUF

pLI 0.989

Z-score 3.71

OE 0.06 (0.02–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.21Z-score

OE missense 0.39 (0.33–0.47)

87 obs / 221.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.27)

0≤0.351.4

Missense OE?0.39 (0.33–0.47)

0≤0.61.4

Synonymous OE?1.33

0≤1.21.6

LoF obs/exp: 1 / 17.9Missense obs/exp: 87 / 221.7Syn Z: -2.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGNB2-related developmental disorderOTHERAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.3491th %ile

LOF

0.78top 5%

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

LOFprediction above median · LOEUF 0.27

GOF1 literature citation · 100% of P/LP are missense

Literature Evidence

GOFA GNB2 gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity.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 28219978 ↗

ClinVar Variant Classifications

109 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic5

VUS61

Likely Benign12

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	7	0	0	7
Likely Pathogenic	0	5	0	0	5
VUS	2	58	1	0	61
Likely Benign	0	2	3	7	12
Benign	0	1	0	1	2
Total	2	73	4	8	87

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap GNB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →