GJB2

gap junction protein beta 2, the group of Gap junction proteins

Basic information

Region (hg38): 13:20187462-20192938

Previous symbols: [ "DFNB1", "DFNA3" ]

Links

ENSG00000165474 ∙ NCBI:2706 ∙ OMIM:121011 ∙ HGNC:4284 ∙ Uniprot:P29033 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive nonsyndromic hearing loss 1A (Strong), mode of inheritance: AR
• ichthyosis, hystrix-like, with hearing loss (Strong), mode of inheritance: AD
• palmoplantar keratoderma-deafness syndrome (Strong), mode of inheritance: AD
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome (Strong), mode of inheritance: AD
• keratoderma hereditarium mutilans (Strong), mode of inheritance: AD
• Bart-Pumphrey syndrome (Strong), mode of inheritance: AD
• KID syndrome (Supportive), mode of inheritance: AD
• palmoplantar keratoderma-deafness syndrome (Supportive), mode of inheritance: AD
• keratoderma hereditarium mutilans (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 1A (Definitive), mode of inheritance: AR
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome (Moderate), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 3A (Strong), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 1A (Definitive), mode of inheritance: AR
• ichthyosis, hystrix-like, with hearing loss (Definitive), mode of inheritance: AD
• Bart-Pumphrey syndrome (Definitive), mode of inheritance: AD
• palmoplantar keratoderma-deafness syndrome (Definitive), mode of inheritance: AD
• keratoderma hereditarium mutilans (Definitive), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 1A (Strong), mode of inheritance: AR
• autosomal dominant nonsyndromic hearing loss 3A (Strong), mode of inheritance: AD
• Bart-Pumphrey syndrome (Strong), mode of inheritance: AD
• hearing loss, autosomal recessive (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 1A; Deafness, digenic; Hystrix-like ichthyosis with deafness; Deafness, autosomal dominant 3A; Bart-Pumphrey syndrome; Keratoderma, palmoplantar, with deafness; Vohwinkel syndrome; Keratitis-icthyosis-deafness syndrome	AD/AR/Digenic	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Oncologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In certain conditions (eg, KID syndrome), infectious and malignant complications may benefit from surveillance leading to microbial prophylaxis and early and aggressive treatment of infections and early detection and treatment of malignancy	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dermatologic; Oncologic; Ophthalmologic	6015974; 1532426; 8010352; 7748756; 9139825; 9529365; 9620796; 10218527; 10369869; 10633135; 10807696; 11298683; 11807148; 12047643; 11960582; 11912510; 11889383; 12372058; 12072059; 11918723; 12560944; 14694360; 15150777; 15482471; 14700667; 16222667; 16380907; 15994881; 15633193; 15691545; 15996214; 16840571; 17041943; 17330861; 993581; 17041943; 19050930; 18843290; 20815033; 20412116
In nonsyndromic deafness, onset of AD disease can be pre or postlingual; In syndromic disease, although skin and other findings may be obvious in some individuals, the syndromic combination of features may not be as readily appreciated as being related to hearing impairment; Digenic inheritance (with GJB3, GJB6) has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GJB2 gene.

• not provided (374 variants)
• Autosomal recessive nonsyndromic hearing loss 1A (261 variants)
• Autosomal dominant nonsyndromic hearing loss 3A (108 variants)
• not specified (106 variants)
• Nonsyndromic genetic hearing loss (71 variants)
• Ichthyosis, hystrix-like, with hearing loss (66 variants)
• Rare genetic deafness (62 variants)
• 8 conditions (59 variants)
• Hearing loss (33 variants)
• Hearing impairment (30 variants)
• Autosomal recessive nonsyndromic hearing loss 1A;Autosomal recessive nonsyndromic hearing loss 1B (15 variants)
• GJB2-related condition (13 variants)
• Inborn genetic diseases (9 variants)
• 7 conditions (7 variants)
• Hearing loss, autosomal recessive (7 variants)
• Mutilating keratoderma (7 variants)
• nonsyndromic sensorineural hearing loss (6 variants)
• Nonsyndromic Deafness (6 variants)
• Palmoplantar keratoderma-deafness syndrome (4 variants)
• Autosomal dominant keratitis-ichthyosis-hearing loss syndrome (4 variants)
• GJB2-Related Disorders (4 variants)
• See cases (3 variants)
• Sensorineural hearing loss disorder (3 variants)
• Ear malformation (3 variants)
• Autosomal recessive nonsyndromic hearing loss 1A;Autosomal dominant nonsyndromic hearing loss 3A (2 variants)
• Deafness (2 variants)
• Knuckle pads, deafness AND leukonychia syndrome (2 variants)
• Autism spectrum disorder (2 variants)
• Autosomal recessive nonsyndromic hearing loss 104 (2 variants)
• Nonsyndromic genetic hearing loss;Hereditary palmoplantar keratoderma (2 variants)
• Progressive sensorineural hearing impairment (2 variants)
• Nonsyndromic Hearing Loss, Recessive (2 variants)
• Bilateral sensorineural hearing impairment (1 variants)
• Hearing impairment;Bilateral sensorineural hearing impairment (1 variants)
• Noonan syndrome 1 (1 variants)
• Autosomal recessive nonsyndromic hearing loss 12 (1 variants)
• Ichthyosis, hystrix-like, with hearing loss;Autosomal dominant keratitis-ichthyosis-hearing loss syndrome (1 variants)
• Nonsyndromic Hearing Loss, Dominant (1 variants)
• IFAP syndrome 1, with or without BRESHECK syndrome (1 variants)
• Neonatal respiratory distress;Pulmonary arterial hypertension;Respiratory distress (1 variants)
• Deafness, digenic, GJB2/GJB6 (1 variants)
• Deafness, digenic, GJB2/GJB3 (1 variants)
• GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss (1 variants)
• Autosomal dominant nonsyndromic hearing loss 3A;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Severe sensorineural hearing impairment (1 variants)
• Autosomal recessive nonsyndromic hearing loss 1B;Autosomal recessive nonsyndromic hearing loss 1A (1 variants)
• Bilateral conductive hearing impairment;Hearing impairment (1 variants)
• 6 conditions (1 variants)
• Keratitis ichthyosis and deafness syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GJB2 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			2	98		100
missense	28	70	78	7	2	185
nonsense	15	14	1			30
start loss	2	3				5
frameshift	26	21				47
inframe indel	2	3	8			13
splice donor/acceptor (+/-2bp)		2	2			4
splice region		1	1			2
non coding			34	6	11	51
Total	73	113	125	111	13

Highest pathogenic variant AF is 0.00941

Variants in GJB2

This is a list of pathogenic ClinVar variants found in the GJB2 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-20187606-ATACT-A		Keratitis ichthyosis and deafness syndrome • Mutilating keratoderma • Nonsyndromic Hearing Loss, Dominant • Ichthyosis, hystrix-like, with hearing loss • Nonsyndromic Hearing Loss, Recessive	Uncertain significance (Jun 14, 2016)
13-20187624-A-G		Autosomal dominant nonsyndromic hearing loss 3A • Ichthyosis, hystrix-like, with hearing loss • Autosomal recessive nonsyndromic hearing loss 1A	Benign (Jan 13, 2018)
13-20187695-A-C		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A	Uncertain significance (Jan 13, 2018)
13-20187704-A-T		Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss	Benign/Likely benign (May 19, 2021)
13-20187749-C-T		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A	Benign (May 12, 2021)
13-20187834-C-A		Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A	Benign (May 12, 2021)
13-20187861-T-C		Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A	Uncertain significance (Jan 13, 2018)
13-20187868-C-T		Ichthyosis, hystrix-like, with hearing loss • Autosomal recessive nonsyndromic hearing loss 1A • Autosomal dominant nonsyndromic hearing loss 3A	Conflicting classifications of pathogenicity (Jan 13, 2018)
13-20187885-T-C		Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss	Conflicting classifications of pathogenicity (Jan 12, 2018)
13-20187922-T-C		Autosomal recessive nonsyndromic hearing loss 1A • Autosomal dominant nonsyndromic hearing loss 3A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 13, 2018)
13-20187970-G-A		Ichthyosis, hystrix-like, with hearing loss • Autosomal recessive nonsyndromic hearing loss 1A • Autosomal dominant nonsyndromic hearing loss 3A	Benign (May 13, 2021)
13-20188101-T-C		Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 12, 2018)
13-20188115-C-T		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A	Conflicting classifications of pathogenicity (Jan 12, 2018)
13-20188222-A-G		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A	Uncertain significance (Jan 13, 2018)
13-20188303-G-T		Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 13, 2018)
13-20188351-T-C		Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A	Uncertain significance (Jan 13, 2018)
13-20188357-A-G		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A	Uncertain significance (Jan 12, 2018)
13-20188419-T-C		Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 13, 2018)
13-20188478-G-A		Autosomal dominant nonsyndromic hearing loss 3A • Ichthyosis, hystrix-like, with hearing loss • Autosomal recessive nonsyndromic hearing loss 1A	Uncertain significance (Jan 13, 2018)
13-20188489-T-G		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A	Uncertain significance (Jan 13, 2018)
13-20188516-C-G		Autosomal recessive nonsyndromic hearing loss 1A • Autosomal dominant nonsyndromic hearing loss 3A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 13, 2018)
13-20188593-C-T		Autosomal recessive nonsyndromic hearing loss 1A • Autosomal dominant nonsyndromic hearing loss 3A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 12, 2018)
13-20188665-T-A		Autosomal recessive nonsyndromic hearing loss 1A • Autosomal dominant nonsyndromic hearing loss 3A • Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (Jan 17, 2018)
13-20188733-T-C		Autosomal dominant nonsyndromic hearing loss 3A • Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss	Benign (Jul 01, 2021)
13-20188786-T-G		Autosomal recessive nonsyndromic hearing loss 1A • Ichthyosis, hystrix-like, with hearing loss • Autosomal dominant nonsyndromic hearing loss 3A • 8 conditions	Uncertain significance (Jul 02, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GJB2	protein_coding	protein_coding	ENST00000382844	1	5429

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.56e-16	0.000154	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.720	161	137	1.17	0.00000846	1481
Missense in Polyphen		70	67.124	1.0428		721
Synonymous	-0.293	64	61.1	1.05	0.00000437	446
Loss of Function	-3.82	17	6.50	2.62	2.82e-7	69

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

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: Deafness, autosomal recessive, 1A (DFNB1A) [MIM:220290]: 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:10830906, ECO:0000269|PubMed:11313763, ECO:0000269|PubMed:11439000, ECO:0000269|PubMed:12121355, ECO:0000269|PubMed:12239718, ECO:0000269|PubMed:12786758, ECO:0000269|PubMed:14722929, ECO:0000269|PubMed:15592461, ECO:0000269|PubMed:15666300, ECO:0000269|PubMed:15994881, ECO:0000269|PubMed:17660464, ECO:0000269|PubMed:17666888, ECO:0000269|PubMed:19384972, ECO:0000269|PubMed:23680645, ECO:0000269|PubMed:28281779, ECO:0000269|PubMed:9328482, ECO:0000269|PubMed:9336442, ECO:0000269|PubMed:9471561, ECO:0000269|PubMed:9529365}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 3A (DFNA3A) [MIM:601544]: 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:10807696, ECO:0000269|PubMed:11313763, ECO:0000269|PubMed:11439000, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:12786758, ECO:0000269|PubMed:19384972, ECO:0000269|PubMed:9620796}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vohwinkel syndrome (VOWNKL) [MIM:124500]: An autosomal dominant disease characterized by hyperkeratosis, constriction on fingers and toes and congenital deafness. {ECO:0000269|PubMed:10369869, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:15954104, ECO:0000269|PubMed:18688874}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratoderma, palmoplantar, with deafness (PPKDFN) [MIM:148350]: An autosomal dominant disorder characterized by the association of palmoplantar hyperkeratosis with progressive, bilateral, high-frequency, sensorineural deafness. {ECO:0000269|PubMed:10633135, ECO:0000269|PubMed:10757647, ECO:0000269|PubMed:12372058, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:15996214, ECO:0000269|PubMed:17993581, ECO:0000269|PubMed:9856479}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratitis-ichthyosis-deafness syndrome (KID syndrome) [MIM:148210]: An autosomal dominant form of ectodermal dysplasia. Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Keratitis-ichthyosis-deafness syndrome is characterized by the association of hyperkeratotic skin lesions with vascularizing keratitis and profound sensorineural hearing loss. Clinical features include deafness, ichthyosis, photophobia, absent or decreased eyebrows, sparse or absent scalp hair, decreased sweating and dysplastic finger and toenails. {ECO:0000269|PubMed:11912510, ECO:0000269|PubMed:12548749, ECO:0000269|PubMed:12752120}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bart-Pumphrey syndrome (BPS) [MIM:149200]: An autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, It shows considerable phenotypic variability. {ECO:0000269|PubMed:15482471, ECO:0000269|PubMed:15952212}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ichthyosis hystrix-like with deafness syndrome (HID syndrome) [MIM:602540]: An autosomal dominant keratinizing disorder characterized by sensorineural deafness and spiky hyperkeratosis affecting the entire skin. HID syndrome is considered to differ from the similar KID syndrome in the extent and time of occurrence of skin symptoms and the severity of the associated keratitis. {ECO:0000269|PubMed:12072059}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Calcium Regulation in the Cardiac Cell;Vesicle-mediated transport;Membrane Trafficking;Transport of connexins along the secretory pathway;Oligomerization of connexins into connexons;Transport of connexons to the plasma membrane;Gap junction assembly;Gap junction trafficking;Gap junction trafficking and regulation (Consensus)

Recessive Scores

• pRec: 0.506

Intolerance Scores

• loftool: 0.163
• rvis_EVS: 0.66
• rvis_percentile_EVS: 84.55

Haploinsufficiency Scores

• pHI: 0.429
• hipred: N
• hipred_score: 0.473
• ghis: 0.429

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gjb2
• 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); reproductive system phenotype; normal 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); embryo phenotype; skeleton phenotype; immune system phenotype; limbs/digits/tail phenotype; 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); growth/size/body region 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); homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype

Zebrafish Information Network

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

Gene ontology

• Biological process: response to ischemia;cell-cell signaling;aging;sensory perception of sound;gap junction assembly;response to estradiol;response to lipopolysaccharide;response to retinoic acid;response to progesterone;cellular response to oxidative stress;response to human chorionic gonadotropin;response to antibiotic;decidualization;inner ear development;transmembrane transport;cellular response to glucagon stimulus;cellular response to dexamethasone stimulus;epididymis development
• Cellular component: endoplasmic reticulum-Golgi intermediate compartment;cytosol;plasma membrane;connexin complex;integral component of membrane;lateral plasma membrane;cell body;perinuclear region of cytoplasm;astrocyte projection
• Molecular function: gap junction channel activity;identical protein binding