GNB5

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

Basic information

Region (hg38): 15:52115099-52191392

Links

ENSG00000069966 ∙ NCBI:10681 ∙ OMIM:604447 ∙ HGNC:4401 ∙ Uniprot:O14775 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• schizophrenia (No Known Disease Relationship), mode of inheritance: Unknown
• language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (Strong), mode of inheritance: AR
• gnb5-related intellectual disability-cardiac arrhythmia syndrome (Supportive), mode of inheritance: AR
• gnb5-related intellectual disability-cardiac arrhythmia syndrome (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
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	AR	Cardiovascular	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	Cardiovascular; Neurologic	27523599; 27677260

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GNB5 gene.

• Gnb5-related intellectual disability-cardiac arrhythmia syndrome (6 variants)
• Gnb5-related intellectual disability-cardiac arrhythmia syndrome;Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (3 variants)
• not provided (3 variants)
• Inborn genetic diseases (3 variants)
• Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (1 variants)
• Attention deficit hyperactivity disorder;Global developmental delay;Delayed speech and language development (1 variants)
• GNB5-related disorder (1 variants)
• LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND CARDIAC ARRHYTHMIA (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GNB5 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				10	5	15
missense	2	1	34	2	1	40
nonsense	2	3				5
start loss						0
frameshift	2	2				4
inframe indel						0
splice donor/acceptor (+/-2bp)	2	2	1			5
splice region			1	1		2
non coding				25	43	68
Total	8	8	35	37	49

Highest pathogenic variant AF is 0.0000131

Variants in GNB5

This is a list of pathogenic ClinVar variants found in the GNB5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-52122834-A-C			Benign (Sep 26, 2018)
15-52122889-T-TAC			Benign (Aug 18, 2019)
15-52122889-T-TACAC			Benign (Aug 21, 2019)
15-52122911-T-C			Benign (Aug 08, 2019)
15-52122977-C-CA			Benign (Sep 04, 2018)
15-52123049-C-CTA			Benign (Mar 29, 2019)
15-52123061-C-A			Benign (Sep 29, 2018)
15-52123079-C-T			Benign (Sep 26, 2018)
15-52124246-T-TA			Benign (Sep 29, 2018)
15-52124357-C-T			Likely benign (Sep 26, 2018)
15-52124394-C-G			Benign (Sep 11, 2018)
15-52124466-C-T			Likely benign (May 24, 2018)
15-52124489-C-G		Gnb5-related intellectual disability-cardiac arrhythmia syndrome	Pathogenic (May 04, 2022)
15-52124497-A-T			Likely benign (Feb 01, 2023)
15-52124516-T-C		Inborn genetic diseases	Uncertain significance (Mar 08, 2024)
15-52124517-C-T		Gnb5-related intellectual disability-cardiac arrhythmia syndrome • Inborn genetic diseases	Uncertain significance (Mar 21, 2023)
15-52124522-G-A			Uncertain significance (Apr 06, 2021)
15-52124524-A-G			Likely benign (Dec 01, 2023)
15-52124529-G-A		Gnb5-related intellectual disability-cardiac arrhythmia syndrome	Likely pathogenic (Aug 10, 2023)
15-52124541-C-T			Uncertain significance (Dec 01, 2021)
15-52124542-G-A			Benign/Likely benign (Jul 27, 2021)
15-52124546-T-A			Uncertain significance (Oct 24, 2023)
15-52124555-C-T		Inborn genetic diseases	Uncertain significance (Jan 29, 2024)
15-52124556-CA-C			Likely pathogenic (Dec 04, 2018)
15-52124557-A-T			Uncertain significance (Jan 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GNB5	protein_coding	protein_coding	ENST00000261837	12	70450

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.36e-8	0.882	125692	0	56	125748	0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.50	167	231	0.722	0.0000133	2569
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000362	0.000362
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000435	0.000435
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000246	0.000237
Middle Eastern	0.000435	0.000435
South Asian	0.000262	0.000261
Other	0.000489	0.000489

dbNSFP

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.
• Pathway: 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);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Endothelin Pathways;Corticotropin-releasing hormone signaling pathway;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;Chemokine signaling pathway;PI3K-Akt Signaling Pathway;Ras Signaling;Calcium Regulation in the Cardiac Cell;Signaling by GPCR;Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding;Signaling by WNT;Signal Transduction;GPCR Dopamine D1like receptor;GPCR Adenosine A2A receptor;Thromboxane signalling through TP receptor;GPCR GroupI metabotropic glutamate receptor;Metabolism of proteins;GPCR signaling-G alpha q;ADP signalling through P2Y purinoceptor 12;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Chaperonin-mediated protein folding;Metabolism;G alpha (s) signalling events;Presynaptic function of Kainate receptors;Activation of kainate receptors upon glutamate binding;Adrenaline,noradrenaline inhibits insulin secretion;Transport of small molecules;Glucagon-like Peptide-1 (GLP1) regulates insulin secretion;Regulation of insulin secretion;Signal amplification;Neuronal System;CRH;Thrombin signalling through proteinase activated receptors (PARs);Glucagon-type ligand receptors;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;Platelet activation, signaling and aggregation;GPCR signaling-G alpha s PKA and ERK;Ca2+ pathway;Beta-catenin independent WNT signaling;ADP signalling through P2Y purinoceptor 1;Hemostasis;Visual signal transduction: Rods;Thromboxane A2 receptor signaling;Protein folding;G-protein activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Opioid Signalling;G alpha (i) signalling events;G alpha (12/13) signalling events;G alpha (z) signalling events;Inactivation, recovery and regulation of the phototransduction cascade;The phototransduction cascade;Visual phototransduction;GPCR signaling-G alpha i;Vasopressin regulates renal water homeostasis via Aquaporins;Aquaporin-mediated transport;G beta:gamma signalling through PLC beta;Prostacyclin signalling through prostacyclin receptor;Integration of energy metabolism;Platelet homeostasis;G alpha (q) signalling events;G beta:gamma signalling through PI3Kgamma;G-protein beta:gamma signalling;GPCR downstream signalling;Visual signal transduction: Cones (Consensus)

Recessive Scores

• pRec: 0.160

Intolerance Scores

• loftool: 0.790
• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.72

Haploinsufficiency Scores

• pHI: 0.106
• hipred: Y
• hipred_score: 0.589
• ghis: 0.587

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.866

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gnb5
• Phenotype: growth/size/body region phenotype; muscle phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: protein folding;signal transduction;dopamine receptor signaling pathway;positive regulation of GTPase activity;negative regulation of voltage-gated calcium channel activity
• Cellular component: nucleus;cytosol;plasma membrane;myelin sheath;presynapse;GTPase activator complex
• Molecular function: GTPase activity;GTPase activator activity;protein binding;G-protein gamma-subunit binding;chaperone binding