GJB6

gap junction protein beta 6, the group of Gap junction proteins

Basic information

Region (hg38): 13:20221962-20232365

Previous symbols: [ "DFNA3", "ED2" ]

Links

ENSG00000121742 ∙ NCBI:10804 ∙ OMIM:604418 ∙ HGNC:4288 ∙ Uniprot:O95452 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Clouston syndrome (Strong), mode of inheritance: AD
• Clouston syndrome (Moderate), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 3B (Moderate), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 1B (Limited), mode of inheritance: AR
• KID syndrome (Supportive), mode of inheritance: AD
• Clouston syndrome (Supportive), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss (Supportive), mode of inheritance: AD
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 1B (Limited), mode of inheritance: AR
• Clouston syndrome (Definitive), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 1B (Limited), mode of inheritance: AR
• autosomal dominant nonsyndromic hearing loss 3B (Limited), mode of inheritance: AD
• Clouston syndrome (Strong), mode of inheritance: AD
• nonsyndromic genetic hearing loss (Refuted Evidence), mode of inheritance: AR
• Clouston syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 1B; Deafness, digenic	AR/Digenic	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dental; Dermatologic	10471490; 11017065; 11807148; 11896458; 15150777; 15994881; 17041943; 18324688; 21465647
Digenic inheritance (eg, with GJB2) has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GJB6 gene.

• Hidrotic ectodermal dysplasia syndrome (2 variants)
• GJB6-related disorder (1 variants)
• Autosomal recessive nonsyndromic hearing loss 1B;Hidrotic ectodermal dysplasia syndrome;X-linked mixed hearing loss with perilymphatic gusher;Autosomal dominant nonsyndromic hearing loss 3B;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Autosomal dominant nonsyndromic hearing loss 3B;Autosomal recessive nonsyndromic hearing loss 1B;Hidrotic ectodermal dysplasia syndrome;X-linked mixed hearing loss with perilymphatic gusher;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• not provided (1 variants)
• Autosomal recessive nonsyndromic hearing loss 1B;Hidrotic ectodermal dysplasia syndrome;Autosomal dominant nonsyndromic hearing loss 3B;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Autosomal dominant nonsyndromic hearing loss 3B;Autosomal recessive nonsyndromic hearing loss 1B;Hidrotic ectodermal dysplasia syndrome;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GJB6 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			4	18		22
missense	2	2	55	6		65
nonsense			3			3
start loss			1			1
frameshift		1	5			6
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region						0
non coding			17	23	26	66
Total	2	3	86	47	26

Highest pathogenic variant AF is 0.00000657

Variants in GJB6

This is a list of pathogenic ClinVar variants found in the GJB6 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-20221981-G-A		Hidrotic ectodermal dysplasia syndrome	Likely benign (Jan 12, 2018)
13-20222067-C-A		Hidrotic ectodermal dysplasia syndrome	Uncertain significance (Jan 12, 2018)
13-20222082-A-C		Hidrotic ectodermal dysplasia syndrome	Likely benign (Jan 13, 2018)
13-20222136-G-A		Hidrotic ectodermal dysplasia syndrome	Uncertain significance (Jan 12, 2018)
13-20222358-C-A		Hidrotic ectodermal dysplasia syndrome	Benign (Jan 13, 2018)
13-20222394-C-G		Hidrotic ectodermal dysplasia syndrome	Benign (Feb 11, 2019)
13-20222467-C-CA		Autosomal recessive nonsyndromic hearing loss 1B;Autosomal dominant nonsyndromic hearing loss 3B;Autosomal recessive nonsyndromic hearing loss 1A;Hidrotic ectodermal dysplasia syndrome;X-linked mixed hearing loss with perilymphatic gusher	Benign/Likely benign (Sep 30, 2021)
13-20222503-G-A		Hidrotic ectodermal dysplasia syndrome	Uncertain significance (Jan 13, 2018)
13-20222670-G-A		Hidrotic ectodermal dysplasia syndrome	Uncertain significance (Jan 12, 2018)
13-20222700-T-C		Autosomal dominant nonsyndromic hearing loss 3B;Autosomal recessive nonsyndromic hearing loss 1A;Hidrotic ectodermal dysplasia syndrome;Autosomal recessive nonsyndromic hearing loss 1B	Uncertain significance (Mar 19, 2024)
13-20222704-G-A			Likely benign (May 16, 2018)
13-20222715-T-C			Uncertain significance (Nov 09, 2022)
13-20222728-A-C		Autosomal recessive nonsyndromic hearing loss 1A;Autosomal recessive nonsyndromic hearing loss 1B;Autosomal dominant nonsyndromic hearing loss 3B;Hidrotic ectodermal dysplasia syndrome	Uncertain significance (Nov 27, 2022)
13-20222739-T-C		Hidrotic ectodermal dysplasia syndrome	Uncertain significance (Apr 27, 2017)
13-20222745-C-T		Inborn genetic diseases	Uncertain significance (Apr 05, 2023)
13-20222753-TC-T			Uncertain significance (Jan 19, 2022)
13-20222758-C-T		Autosomal recessive nonsyndromic hearing loss 1B;Autosomal dominant nonsyndromic hearing loss 3B;Hidrotic ectodermal dysplasia syndrome;Autosomal recessive nonsyndromic hearing loss 1A	Likely benign (Jul 17, 2021)
13-20222765-C-T			Uncertain significance (Oct 03, 2024)
13-20222767-CTCCTTTAGGG-T			Uncertain significance (Jan 26, 2024)
13-20222780-T-C			Uncertain significance (Aug 31, 2020)
13-20222786-G-T		Autosomal recessive nonsyndromic hearing loss 1B;Autosomal dominant nonsyndromic hearing loss 3B;Hidrotic ectodermal dysplasia syndrome;Autosomal recessive nonsyndromic hearing loss 1A	Uncertain significance (Aug 27, 2022)
13-20222791-A-AT		not specified • Autosomal recessive nonsyndromic hearing loss 1A;Autosomal recessive nonsyndromic hearing loss 1B;Autosomal dominant nonsyndromic hearing loss 3B;Hidrotic ectodermal dysplasia syndrome	Conflicting classifications of pathogenicity (Jan 01, 2024)
13-20222793-T-A		Inborn genetic diseases	Uncertain significance (Feb 26, 2024)
13-20222801-G-A		Hidrotic ectodermal dysplasia syndrome • Autosomal recessive nonsyndromic hearing loss 1B;Autosomal recessive nonsyndromic hearing loss 1A;Autosomal dominant nonsyndromic hearing loss 3B;Hidrotic ectodermal dysplasia syndrome • GJB6-related disorder	Uncertain significance (Dec 13, 2023)
13-20222809-T-C		Hidrotic ectodermal dysplasia syndrome • Autosomal recessive nonsyndromic hearing loss 1B;Autosomal dominant nonsyndromic hearing loss 3B;Hidrotic ectodermal dysplasia syndrome;Autosomal recessive nonsyndromic hearing loss 1A	Conflicting classifications of pathogenicity (Aug 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GJB6	protein_coding	protein_coding	ENST00000356192	1	10425

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.66e-7	0.132	125554	0	194	125748	0.000772

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.453	134	150	0.896	0.00000863	1737
Missense in Polyphen		47	62.111	0.75671		749
Synonymous	-0.493	69	64.0	1.08	0.00000429	502
Loss of Function	-0.211	10	9.31	1.07	6.67e-7	84

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000478	0.000478
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.00158	0.00158
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.00114	0.00114
Middle Eastern	0.00158	0.00158
South Asian	0.000294	0.000294
Other	0.00179	0.00179

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: Ectodermal dysplasia 2, Clouston type (ECTD2) [MIM:129500]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD2 is an autosomal dominant condition characterized by atrichosis, nail hypoplasia and deformities, hyperpigmentation of the skin, normal teeth, normal sweat and sebaceous gland function. Palmoplantar hyperkeratosis is a frequent feature. Hearing impairment has been detected in few cases. {ECO:0000269|PubMed:11017065, ECO:0000269|PubMed:11874494}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 1B (DFNB1B) [MIM:612645]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:11807148, ECO:0000269|PubMed:15994881}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 3B (DFNA3B) [MIM:612643]: A form of non-syndromic sensorineural hearing loss characterized by a variable phenotype, ranging from bilateral middle to high frequency hearing loss to profound sensorineural deafness. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:10471490}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Hair Follicle Development- Induction (Part 1 of 3);Calcium Regulation in the Cardiac Cell (Consensus)

Recessive Scores

• pRec: 0.322

Intolerance Scores

• loftool: 0.0864
• rvis_EVS: 0.26
• rvis_percentile_EVS: 70.26

Haploinsufficiency Scores

• pHI: 0.0532
• hipred: N
• hipred_score: 0.392
• ghis: 0.442

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.450

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gjb6
• Phenotype: homeostasis/metabolism phenotype; endocrine/exocrine gland 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); 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); hearing/vestibular/ear phenotype; 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: cx30.3
• Affected structure: sagitta
• Phenotype tag: abnormal
• Phenotype quality: decreased width

Gene ontology

• Biological process: apoptotic process;cell communication;aging;sensory perception of sound;negative regulation of cell population proliferation;response to lipopolysaccharide;ear morphogenesis;inner ear development;response to electrical stimulus;cellular response to glucose stimulus
• Cellular component: cytosol;connexin complex;integral component of membrane;apical plasma membrane;cell junction