GNB5

protein-coding

G protein subunit beta 5, the group of G protein subunits beta|WD repeat domain containing

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. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Jul 2008]

MANE transcript

NM_016194.4

Inheritance

ClinVar variants

P:31U:94B:23

Top phenotype

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

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr15:52,115,100-52,191,392

External References & Databases

Ensembl (ENSG00000069966)

Transcript & Mutation Effects

hg38 • Region Span ~76.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014953

Submitter: PanelApp Australia

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014953

Submitter: Labcorp Genetics (formerly Invitae)

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014953

Submitter: G2P

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014953

Submitter: Orphanet

language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014957

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

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 arrhythmiaAR

Manifestation: Cardiovascular; Neurologic

Intervention: Cardiovascular

Rationale: Among other findings, individuals have been described with cardiac abnormalities, including sick sinus syndrome with bradycardia, escape beats, and other arrhythmias, and awareness may allow early diagnosis and management such as via pacemaker placement

Refs: 27523599; 27677260

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNB5 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 93

Inborn genetic diseasesTotal: 64

Gnb5-related intellectual disability-cardiac arrhythmia syndromeTotal: 26

not specifiedTotal: 25

Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmiaTotal: 9

GNB5-related disorderTotal: 8

Global developmental delayTotal: 2

Cardiovascular phenotypeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016194.4. 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			19 clinvar	2 clinvar	22
missense	3 clinvar	2 clinvar	84 clinvar	2 clinvar		91
nonsense	3 clinvar	5 clinvar	1 clinvar			9
start loss						0
frameshift	7 clinvar	2 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	3 clinvar	5 clinvar	8 clinvar			16
Total	17	14	94	21	2	148

Highest pathogenic variant AF is 0.00008000327

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016194.4	RefSeq	NP_057278.2	12	MANE Select
ENST00000261837.12	Ensembl	ENSP00000261837.7	12	MANE Select
NM_001379343.1	RefSeq	NP_001366272.1	10	Standard
NM_006578.4	RefSeq	NP_006569.1	11	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
signal transduction
dopamine receptor signaling pathway
positive regulation of GTPase activity
negative regulation of voltage-gated calcium channel activity

Molecular Function

GTPase activity
GTPase activator activity
protein binding
G-protein gamma-subunit binding
chaperone binding

Cellular Component

nucleus
cytosol
plasma membrane
myelin sheath
presynapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261837
Coding exons: 12
Length: 70450
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	1.50	167	231	0.722	0.0000133	2569
Missense (PolyPhen)		69	118.13	0.58412		1310
Synonymous	0.128	93	94.6	0.983	0.00000616	733
Loss of Function	1.66	15	23.7	0.632	0.00000121	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00024	rare
South Asian	0.00026	0.00026	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Enhances GTPase-activating protein (GAP) activity of regulator of G protein signaling (RGS) proteins, hence involved in the termination of the signaling initiated by the G protein coupled receptors (GPCRs) by accelerating the GTP hydrolysis on the G-alpha subunits, thereby promoting their inactivation (Probable). Increases RGS9 GTPase-activating protein (GAP) activity, hence contributes to the deactivation of G protein signaling initiated by D(2) dopamine receptors (PubMed:27677260). May play an important role in neuronal signaling, including in the parasympathetic, but not sympathetic, control of heart rate (By similarity). {ECO:0000250|UniProtKB:A1L271, ECO:0000269|PubMed:27677260, ECO:0000305}.;
Disease: DISEASE: Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (LADCI) [MIM:617182]: An autosomal recessive neurodevelopmental disorder characterized by speech impairment and variable expressivity of attention deficit hyperactivity disorder. Some patients manifest developmental and motor delay, hypotonia, and sinus-node dysfunction. {ECO:0000269|PubMed:27523599, ECO:0000269|PubMed:27677260}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.790
RVIS EVS: -0.58
RVIS percentile EVS: 18.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.866

Gene Damage Prediction

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