CLCN2

chloride voltage-gated channel 2, the group of Chloride voltage-gated channels

Basic information

Region (hg38): 3:184346185-184361650

Links

ENSG00000114859 ∙ NCBI:1181 ∙ OMIM:600570 ∙ HGNC:2020 ∙ Uniprot:P51788 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• epilepsy, idiopathic generalized, susceptibility to, 11 (Strong), mode of inheritance: AD
• leukoencephalopathy with mild cerebellar ataxia and white matter edema (Strong), mode of inheritance: AR
• leukoencephalopathy with mild cerebellar ataxia and white matter edema (Moderate), mode of inheritance: AR
• familial hyperaldosteronism type II (Moderate), mode of inheritance: AD
• familial hyperaldosteronism type II (Supportive), mode of inheritance: AD
• leukoencephalopathy with mild cerebellar ataxia and white matter edema (Supportive), mode of inheritance: AR
• leukoencephalopathy with mild cerebellar ataxia and white matter edema (Strong), mode of inheritance: AR
• leukoencephalopathy with mild cerebellar ataxia and white matter edema (Definitive), mode of inheritance: AR
• epilepsy (Refuted Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperaldosteronism, familial, type II	AD	Endocrine	The condition may manifest with features of hyperadolsteronism including hypertension and hypokalemia, and awareness may allow prompt medical management (eg, with spironolactone)	Endocrine; Neurologic	10888596; 12612585; 19710712; 19191339; 20037607; 23707145; 29403011; 29403012
Functional proof of pathogenicity in reported epilepsy-related dominant conditions is controversial; As with other forms of epilepsy, optimal seizure control is advantageous

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN2 gene.

• Leukoencephalopathy with mild cerebellar ataxia and white matter edema (7 variants)
• not provided (6 variants)
• CLCN2-related disorder (2 variants)
• Familial hyperaldosteronism type II (1 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 11;Familial hyperaldosteronism type II;Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN2 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	68	4	76
missense	1	3	181	17	3	205
nonsense	3	5				8
start loss						0
frameshift	8	2	1			11
inframe indel					1	1
splice donor/acceptor (+/-2bp)	1	6	1			8
splice region			13	26	1	40
non coding			2	41	14	57
Total	13	16	189	126	22

Highest pathogenic variant AF is 0.0000131

Variants in CLCN2

This is a list of pathogenic ClinVar variants found in the CLCN2 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-184346596-C-T		CLCN2-related disorder	Benign (Nov 05, 2019)
3-184346598-C-T		CLCN2-related disorder	Likely benign (Mar 27, 2019)
3-184346609-T-C			Likely benign (Dec 21, 2023)
3-184346612-G-A			Likely benign (Jan 01, 2023)
3-184346620-C-T		See cases • Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 17, 2023)
3-184346621-G-A			Likely benign (Jan 13, 2024)
3-184346623-C-T		Inborn genetic diseases	Uncertain significance (Nov 10, 2022)
3-184346624-G-A			Likely benign (Jan 25, 2024)
3-184346629-C-T			Uncertain significance (Nov 17, 2023)
3-184346630-G-A			Likely benign (Sep 29, 2022)
3-184346646-C-T			Likely benign (Oct 17, 2023)
3-184346661-C-T		Leukoencephalopathy with mild cerebellar ataxia and white matter edema;Familial hyperaldosteronism type II;Epilepsy, idiopathic generalized, susceptibility to, 11 • Inborn genetic diseases	Uncertain significance (Jun 17, 2024)
3-184346672-C-T			Likely benign (Aug 24, 2022)
3-184346680-G-C		Epilepsy, idiopathic generalized, susceptibility to, 11 • Epilepsy, idiopathic generalized, susceptibility to, 11;Familial hyperaldosteronism type II;Leukoencephalopathy with mild cerebellar ataxia and white matter edema	Uncertain significance (May 25, 2022)
3-184346680-G-T		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)
3-184346703-G-A			Uncertain significance (Jun 01, 2016)
3-184346710-T-G		Familial hyperaldosteronism type II	Pathogenic (Aug 10, 2018)
3-184346724-C-T			Uncertain significance (Jan 26, 2022)
3-184346730-C-T			Uncertain significance (Apr 01, 2022)
3-184346747-C-T			Likely benign (Nov 24, 2023)
3-184346749-G-A		Inborn genetic diseases	Uncertain significance (Apr 19, 2024)
3-184346753-G-A			Likely benign (Jan 26, 2024)
3-184346756-T-C		not specified	Likely benign (Jun 12, 2024)
3-184346768-T-C			Likely benign (Mar 21, 2022)
3-184346775-A-C			Uncertain significance (Mar 30, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN2	protein_coding	protein_coding	ENST00000265593	24	15467

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.55e-12	0.998	125653	0	95	125748	0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.654	494	537	0.921	0.0000364	5763
Missense in Polyphen		179	215.59	0.83029		2322
Synonymous	-0.971	229	211	1.08	0.0000134	1906
Loss of Function	2.83	26	46.9	0.554	0.00000265	513

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00114	0.00113
Ashkenazi Jewish	0.00	0.00
East Asian	0.000111	0.000109
Finnish	0.0000924	0.0000462
European (Non-Finnish)	0.000514	0.000501
Middle Eastern	0.000111	0.000109
South Asian	0.000327	0.000327
Other	0.000490	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. {ECO:0000269|PubMed:19153159, ECO:0000269|PubMed:19191339}.
• Disease: DISEASE: Epilepsy, idiopathic generalized 11 (EIG11) [MIM:607628]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. {ECO:0000269|PubMed:19191339}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Juvenile absence epilepsy 2 (JAE2) [MIM:607628]: A subtype of idiopathic generalized epilepsy characterized by onset occurring around puberty, absence seizures, generalized tonic- clonic seizures (GTCS), GTCS on awakening, and myoclonic seizures. {ECO:0000269|PubMed:19710712}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Juvenile myoclonic epilepsy 8 (EJM8) [MIM:607628]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269|PubMed:19191339}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Leukoencephalopathy with ataxia (LKPAT) [MIM:615651]: An autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles, suggesting myelin microvacuolation. Clinical features include ataxia and unstable gait. More variable abnormalities may include visual field defects, headaches, and learning disabilities. {ECO:0000269|PubMed:23707145}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mineral absorption - Homo sapiens (human);Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.187

Intolerance Scores

• loftool: 0.0114
• rvis_EVS: 0.5
• rvis_percentile_EVS: 79.66

Haploinsufficiency Scores

• pHI: 0.196
• hipred: N
• hipred_score: 0.476
• ghis: 0.461

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.220

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clcn2
• Phenotype: endocrine/exocrine gland phenotype; cellular 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; reproductive system phenotype; pigmentation phenotype; digestive/alimentary 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; immune system phenotype

Zebrafish Information Network

• Gene name: clcn2c
• Affected structure: chloride transport
• Phenotype tag: abnormal
• Phenotype quality: process quality

Gene ontology

• Biological process: regulation of aldosterone biosynthetic process;ion transmembrane transport;regulation of ion transmembrane transport;retina development in camera-type eye;cell differentiation involved in salivary gland development;chloride transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;chloride channel complex
• Molecular function: voltage-gated chloride channel activity