GJC2

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

Basic information

Region (hg38): 1:228149929-228159826

Previous symbols: [ "GJA12" ]

Links

ENSG00000198835 ∙ NCBI:57165 ∙ OMIM:608803 ∙ HGNC:17494 ∙ Uniprot:Q5T442 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lymphatic malformation 3 (Moderate), mode of inheritance: AD
• hereditary spastic paraplegia 44 (Definitive), mode of inheritance: AD
• hypomyelinating leukodystrophy 2 (Definitive), mode of inheritance: AR
• hypomyelinating leukodystrophy 2 (Definitive), mode of inheritance: AR
• lymphatic malformation (Supportive), mode of inheritance: AD
• hypomyelinating leukodystrophy 2 (Supportive), mode of inheritance: AR
• hereditary spastic paraplegia 44 (Supportive), mode of inheritance: AR
• lymphatic malformation 3 (Strong), mode of inheritance: AD
• hypomyelinating leukodystrophy 2 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 44 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lymphedema malformation 3; Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating, 2	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Cardiovascular; Dermatologic; Neurologic	15192806; 16969684; 18094336; 19056803; 20513814; 20537300; 21266381; 21959080; 22610664; 22669416; 23143715; 24374284
Individuals with Lymphedema have been described with recurrent skin infections

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GJC2 gene.

• Spastic paraplegia (180 variants)
• not provided (66 variants)
• Inborn genetic diseases (30 variants)
• Hypomyelinating leukodystrophy 2 (30 variants)
• Hereditary spastic paraplegia (19 variants)
• not specified (9 variants)
• Lymphatic malformation 3 (5 variants)
• Hereditary spastic paraplegia 44 (5 variants)
• Hereditary spastic paraplegia 44;Hypomyelinating leukodystrophy 2;Lymphatic malformation 3 (2 variants)
• Abnormality of the nervous system (2 variants)
• Pelizaeus-Merzbacher disease (1 variants)
• Dystonic disorder (1 variants)
• See cases (1 variants)
• Spastic ataxia (1 variants)
• Lymphatic malformation 3;Hereditary spastic paraplegia 44;Hypomyelinating leukodystrophy 2 (1 variants)
• Intellectual disability (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GJC2 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			9	49	4	62
missense	3	11	131	1		146
nonsense	5	4				9
start loss						0
frameshift	9	14	1			24
inframe indel			11			11
splice donor/acceptor (+/-2bp)	1					1
splice region			1			1
non coding				5	4	9
Total	18	29	152	55	8

Highest pathogenic variant AF is 0.0000165

Variants in GJC2

This is a list of pathogenic ClinVar variants found in the GJC2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-228150007-G-C		Pelizaeus-Merzbacher disease	Uncertain significance (Dec 30, 2017)
1-228150008-G-C		Spastic paraplegia	Pathogenic (Mar 19, 2022)
1-228150075-C-T			Likely benign (Nov 23, 2019)
1-228157547-C-G			Likely benign (Jun 02, 2021)
1-228157700-TAAGTGCAGGCCCCTGGC-T			Likely benign (Jun 23, 2021)
1-228157737-C-A			Uncertain significance (Mar 02, 2018)
1-228157745-G-C		not specified	Benign (Mar 29, 2016)
1-228157749-G-C			Benign (Mar 16, 2019)
1-228157753-G-C		not specified	Benign (Mar 16, 2019)
1-228157769-T-G		Spastic paraplegia	Uncertain significance (Nov 15, 2021)
1-228157775-G-A			Likely pathogenic (Jan 11, 2016)
1-228157781-TC-AA			Pathogenic (Jan 03, 2019)
1-228157785-G-C		Spastic paraplegia	Likely benign (Dec 02, 2021)
1-228157787-C-T		Spastic paraplegia	Uncertain significance (Jul 26, 2022)
1-228157788-GC-AA		Spastic paraplegia	Likely benign (Jun 04, 2022)
1-228157790-G-A		Spastic paraplegia	Uncertain significance (Jun 08, 2022)
1-228157790-G-C		Lymphatic malformation 3	Uncertain significance (Mar 01, 2023)
1-228157793-T-C		Spastic paraplegia	Uncertain significance (Feb 12, 2021)
1-228157800-G-A		Spastic paraplegia	Likely benign (Dec 07, 2023)
1-228157805-T-TC		Hypomyelinating leukodystrophy 2	Likely pathogenic (-)
1-228157809-C-T		Spastic paraplegia • GJC2-related disorder	Likely benign (Aug 19, 2023)
1-228157820-C-T		Hypomyelinating leukodystrophy 2	Uncertain significance (-)
1-228157826-T-TGGGCAAGGTGTGGC		Spastic paraplegia	Pathogenic (Dec 02, 2023)
1-228157835-TG-T		Hypomyelinating leukodystrophy 2	Likely pathogenic (Jan 01, 2014)
1-228157838-G-A		Inborn genetic diseases	Pathogenic (Nov 19, 2015)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GJC2	protein_coding	protein_coding	ENST00000366714	1	9975

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0104	0.842	125500	0	8	125508	0.0000319

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.87	173	258	0.672	0.0000191	2696
Missense in Polyphen		82	146.16	0.56101		1389
Synonymous	0.516	121	128	0.942	0.0000105	986
Loss of Function	1.17	4	7.45	0.537	3.22e-7	87

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000182	0.000181
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000374	0.0000353
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. May play a role in myelination in central and peripheral nervous systems. {ECO:0000269|PubMed:15192806}.
• Disease: DISEASE: Spastic paraplegia 44, autosomal recessive (SPG44) [MIM:613206]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:19056803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lymphedema, hereditary, 1C (LMPH1C) [MIM:613480]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. {ECO:0000269|PubMed:20537300}. 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: 0.138

Haploinsufficiency Scores

• pHI: 0.120
• hipred: Y
• hipred_score: 0.697
• ghis: 0.614

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.374

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gjc2
• Phenotype: immune system 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); vision/eye phenotype; hematopoietic 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype

Gene ontology

• Biological process: regulation of protein phosphorylation;cell-cell signaling;brain development;response to toxic substance;positive regulation of gene expression;cell communication by electrical coupling;transmembrane transport;positive regulation of oligodendrocyte progenitor proliferation;positive regulation of calcium ion transmembrane transport;negative regulation of G1/S transition of mitotic cell cycle
• Cellular component: gap junction;connexin complex;integral component of membrane;paranode region of axon;perikaryon;myelin sheath;proximal neuron projection
• Molecular function: gap junction channel activity involved in cell communication by electrical coupling