GJB3

gap junction protein beta 3, the group of Gap junction proteins

Basic information

Region (hg38): 1:34781213-34786369

Previous symbols: [ "DFNA2", "EKV" ]

Links

ENSG00000188910 ∙ NCBI:2707 ∙ OMIM:603324 ∙ HGNC:4285 ∙ Uniprot:O75712 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant nonsyndromic hearing loss 2B (Limited), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 1 (Strong), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 1 (Strong), mode of inheritance: AR
• erythrokeratodermia variabilis (Supportive), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss (Supportive), mode of inheritance: AD
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• neuropathy with hearing impairment (Supportive), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 1 (Strong), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 2B (Moderate), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 2B (Limited), mode of inheritance: Unknown
• erythrokeratodermia variabilis et progressiva 1 (Strong), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 1 (Strong), mode of inheritance: AR
• erythrokeratodermia variabilis (Definitive), mode of inheritance: AD
• nonsyndromic genetic hearing loss (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive; Deafness, autosomal dominant, with peripheral neuropathy; Deafness digenic	AD/Digenic	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Dermatologic; Neurologic	1828175; 9843209; 9843210; 10594760; 10798362; 11175305; 12019212; 12452892; 19050930
Digenic inheritance (with GJB2) has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GJB3 gene.

• not provided (125 variants)
• Erythrokeratodermia variabilis et progressiva 1 (73 variants)
• not specified (24 variants)
• Inborn genetic diseases (12 variants)
• Autosomal dominant nonsyndromic hearing loss 2B (4 variants)
• Nonsyndromic Hearing Loss, Dominant (3 variants)
• GJB3-related condition (2 variants)
• Autosomal recessive nonsyndromic hearing loss 1A;Autosomal dominant nonsyndromic hearing loss 2B;Erythrokeratodermia variabilis et progressiva 1 (2 variants)
• Autosomal dominant nonsyndromic hearing loss 2B;Erythrokeratodermia variabilis et progressiva 1;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Deafness, autosomal dominant, with peripheral neuropathy (1 variants)
• Erythrokeratodermia variabilis et progressiva 1;Autosomal dominant nonsyndromic hearing loss 2B;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Hearing impairment (1 variants)
• Autosomal dominant nonsyndromic hearing loss 2B;Autosomal recessive nonsyndromic hearing loss 1A;Erythrokeratodermia variabilis et progressiva 1 (1 variants)
• Nonsyndromic Deafness (1 variants)
• Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Deafness, digenic, GJB2/GJB3 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GJB3 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			3	23	4	30
missense	1	4	64	6	2	77
nonsense			7			7
start loss						0
frameshift			3			3
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			26	2	13	41
Total	1	4	104	31	19

Highest pathogenic variant AF is 0.0000854

Variants in GJB3

This is a list of pathogenic ClinVar variants found in the GJB3 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-34781324-G-C		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Apr 27, 2017)
1-34781327-T-C		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 15, 2018)
1-34781397-C-T		Erythrokeratodermia variabilis et progressiva 1	Benign (Jan 13, 2018)
1-34781405-G-A		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 13, 2018)
1-34781406-C-G		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 12, 2018)
1-34781421-G-A		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 13, 2018)
1-34781497-T-C		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 13, 2018)
1-34781511-C-G		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 12, 2018)
1-34781519-C-A		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 13, 2018)
1-34781573-G-A		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 12, 2018)
1-34781627-G-A		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 12, 2018)
1-34781645-T-C		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 13, 2018)
1-34781654-C-T		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Apr 27, 2017)
1-34781663-C-G		Erythrokeratodermia variabilis et progressiva 1	Benign (Dec 07, 2018)
1-34781711-C-T		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 12, 2018)
1-34781734-C-T		Erythrokeratodermia variabilis et progressiva 1	Uncertain significance (Jan 13, 2018)
1-34781764-G-A		Erythrokeratodermia variabilis et progressiva 1	Benign (Jan 12, 2018)
1-34784692-A-G			Benign (Jun 16, 2018)
1-34784745-C-T		Erythrokeratodermia variabilis et progressiva 1	Likely benign (Jan 12, 2018)
1-34784759-C-T		not specified • GJB3-related disorder	Conflicting classifications of pathogenicity (Mar 25, 2020)
1-34784760-G-A		Erythrokeratodermia variabilis et progressiva 1	Conflicting classifications of pathogenicity (Jun 21, 2022)
1-34784770-G-A		Autosomal recessive nonsyndromic hearing loss 1A	Pathogenic (Feb 26, 2019)
1-34784795-C-T			Likely benign (Jan 28, 2024)
1-34784796-G-A			Likely pathogenic (Mar 30, 2023)
1-34784796-G-C		Erythrokeratodermia variabilis et progressiva 1	Pathogenic (Dec 01, 1998)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GJB3	protein_coding	protein_coding	ENST00000373366	1	5181

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00218	0.770	125690	0	58	125748	0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.526	187	168	1.11	0.0000121	1742
Missense in Polyphen		92	85.298	1.0786		921
Synonymous	0.885	65	74.7	0.870	0.00000573	565
Loss of Function	0.958	5	7.91	0.632	4.37e-7	72

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000275	0.000275
Ashkenazi Jewish	0.0000995	0.0000992
East Asian	0.00141	0.00141
Finnish	0.00	0.00
European (Non-Finnish)	0.000124	0.000123
Middle Eastern	0.00141	0.00141
South Asian	0.000359	0.000359
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
• Disease: DISEASE: Erythrokeratodermia variabilis et progressiva 1 (EKVP1) [MIM:133200]: A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. {ECO:0000269|PubMed:10594760, ECO:0000269|PubMed:10798362, ECO:0000269|PubMed:9843209}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 2B (DFNA2B) [MIM:612644]: A form of non-syndromic sensorineural deafness characterized by progressive high frequency hearing loss in adulthood, with milder expression in females. {ECO:0000269|PubMed:9843210}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Calcium Regulation in the Cardiac Cell (Consensus)

Recessive Scores

• pRec: 0.164

Intolerance Scores

• loftool: 0.107
• rvis_EVS: 0.2
• rvis_percentile_EVS: 67.3

Haploinsufficiency Scores

• pHI: 0.130
• hipred: N
• hipred_score: 0.300
• ghis: 0.553

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.156

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gjb3
• Phenotype: homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); embryo phenotype; immune system phenotype; 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); hematopoietic system phenotype; 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)

Gene ontology

• Biological process: in utero embryonic development;placenta development;cell communication;spermatogenesis;skin development;transmembrane transport;cellular response to retinoic acid
• Cellular component: cytoplasm;gap junction;connexin complex;integral component of membrane;cell junction;intracellular membrane-bounded organelle
• Molecular function: gap junction channel activity