GNB3

protein-coding

G protein subunit beta 3, the group of WD repeat domain containing|G protein subunits beta

Gene summary

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 which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

MANE transcript

NM_002075.4

Inheritance

AR, AD

ClinVar variants

P:1U:190B:71

Top phenotype

Night blindness, congenital stationary, type 1H

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr12:6,839,954-6,847,393

External References & Databases

Ensembl (ENSG00000111664)

Transcript & Mutation Effects

hg38 • Region Span ~7.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital stationary night blindness 1HSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014872

Submitter: PanelApp Australia

congenital stationary night blindness 1HLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014872

Submitter: G2P

congenital stationary night blindness 1HLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014872

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital stationary night blindnessSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016293

Submitter: Orphanet

congenital stationary night blindness 1HLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014872

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Night blindness, congenital stationary, type 1HAR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27063057

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNB3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 341

Inborn genetic diseasesTotal: 51

Congenital stationary night blindness 1HTotal: 4

GNB3-related conditionTotal: 2

Essential hypertension, geneticTotal: 1

Retinal dystrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002075.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	62 clinvar	7 clinvar	71
missense			164 clinvar	2 clinvar		166
nonsense	1 clinvar		7 clinvar			8
start loss			1 clinvar			1
frameshift			10 clinvar			10
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	1	0	190	64	7	262

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002075.4	RefSeq	NP_002066.1	9	MANE Select
ENST00000229264.8	Ensembl	ENSP00000229264.3	9	MANE Select
NM_001297571.2	RefSeq	NP_001284500.1	9	Standard
ENST00000435982.6	Ensembl	ENSP00000414734.2	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)

Biological Process

protein folding
cell volume homeostasis
G protein-coupled receptor signaling pathway
regulation of blood pressure
regulation of gene expression

Molecular Function

GTPase activity
protein binding
spectrin binding
GTPase binding

Cellular Component

cytosol
plasma membrane
dendrite
cell body
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000229264
Coding exons: 9
Length: 7440
Individuals with no LoFs: 125692
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125748
p: 0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	175	219	0.801	0.0000137	2230
Missense (PolyPhen)		56	75.972	0.73711		773
Synonymous	-0.0823	88	87.0	1.01	0.00000602	664
Loss of Function	0.322	17	18.5	0.919	9.72e-7	191

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00044	0.00042	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein- effector interaction.;
Disease: DISEASE: Night blindness, congenital stationary, 1H (CSNB1H) [MIM:617024]: A form of congenital stationary night blindness, a non-progressive retinal disorder characterized by impaired night vision or in dim light, with good vision only on bright days. CSNB1H patients present with childhood-onset night blindness and middle age-onset photophobia, but have near-normal vision and do not exhibit nystagmus or high myopia. CSNB1H inheritance is autosomal recessive. {ECO:0000269|PubMed:27063057}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.281

Intolerance Scores

LoFtool: 0.710
RVIS EVS: -0.4
RVIS percentile EVS: 26.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.517

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium