GNB2

protein-coding

G protein subunit beta 2, 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. 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]

MANE transcript

NM_005273.4

Inheritance

ClinVar variants

P:12U:77B:18

Top phenotype

Sick sinus syndrome 4; Neurodevelopmental disorder with hypotonia and dysmorphic facies

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr7:100,673,567-100,679,174

External References & Databases

Ensembl (ENSG00000172354)

Transcript & Mutation Effects

hg38 • Region Span ~5.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859185

Submitter: PanelApp Australia

sick sinus syndrome 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0859173

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*GNB2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Fukuda et al., PMID: 31698099). Clinical features observed in affected individuals include intellectual disability, developmental delay, hypotonia, dysmorphism, and autism. Less common findings include epilepsy and cardiac malformation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities: sick sinus syndrome 4 (OMIM:619464) and neurodevelopmental disorder with hypotonia and dysmorphic facies (OMIM:619503). At least 7 missense variants have been reported in humans. The mechanism of pathogenicity appears to be loss of function, caused by perturbations in the interaction surface of the alpha and beta subunits of the GPCR protein, leading to attenuated expression of the beta subunit bound to and activating downstream effectors (PMID: 34183358). This gene-disease relationship is also supported by delayed neuronal migration and morphogenesis in Gβ2 knockdown mice (PMID: 28334111). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date March 26th, 2026 (SOP Version 12).

neurodevelopmental disorder with hypotonia and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859185

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with hypotonia and dysmorphic faciesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859185

Submitter: G2P

Clinical Genomic Database (CGD)

Sick sinus syndrome 4; Neurodevelopmental disorder with hypotonia and dysmorphic faciesAD

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular; Renal

Rationale: Individuals with Sick sinus syndrome have been described with arrhthymias, and awareness may allow prompt diagnosis and management (eg, pacemaker implantation has been described); Among other features, Neurodevelopmental disorder with hypotonia and dysmorphic facies can include congenital cardiovascular and renal anomalies, which may require medical and/or surgical interventions to help manage sequelae

Refs: 28219978; 31698099; 33971351; 34183358

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNB2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 55

Inborn genetic diseasesTotal: 33

Neurodevelopmental disorder with hypotonia and dysmorphic faciesTotal: 14

not specifiedTotal: 10

GNB2-related disorderTotal: 7

Sick sinus syndrome 4Total: 2

Paediatric disordersTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005273.4. 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			1 clinvar	14 clinvar	1 clinvar	16
missense	5 clinvar	7 clinvar	65 clinvar	2 clinvar	1 clinvar	80
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	5	7	77	16	2	107

Highest pathogenic variant AF is 0.00003036451

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005273.4	RefSeq	NP_005264.2	9	MANE Select
ENST00000303210.9	Ensembl	ENSP00000305260.4	9	MANE Select
ENST00000393924.1	Ensembl	ENSP00000377501.1	9	Standard
ENST00000393924.2	Ensembl	ENSP00000377501.1	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
G protein-coupled receptor signaling pathway

Molecular Function

GTPase activity
calcium channel regulator activity
protein binding
protein-containing complex binding
GTPase binding

Cellular Component

extracellular space
lysosomal membrane
cytosol
plasma membrane
focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303210
Coding exons: 9
Length: 5644
Individuals with no LoFs: 125687
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125689
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.21	87	222	0.393	0.0000147	2221
Missense (PolyPhen)		14	76.522	0.18295		794
Synonymous	-2.58	129	96.7	1.33	0.00000727	678
Loss of Function	3.71	1	17.9	0.0558	9.53e-7	183

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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.;

Recessive Scores

pRec: 0.142

Intolerance Scores

RVIS EVS: -0.49
RVIS percentile EVS: 22.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.903

Gene Damage Prediction

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