CLCN6

chloride voltage-gated channel 6, the group of Chloride voltage-gated channels

Basic information

Region (hg38): 1:11806096-11848079

Links

ENSG00000011021 ∙ NCBI:1185 ∙ OMIM:602726 ∙ HGNC:2024 ∙ Uniprot:P51797 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities (Limited), mode of inheritance: AD
• neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities	AD	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	Neurologic	33217309

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN6 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN6 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	171	17	192
missense			339	7	1	347
nonsense			9			9
start loss						0
frameshift			10			10
inframe indel			11			11
splice donor/acceptor (+/-2bp)			6			6
splice region			20	42	4	66
non coding			6	138	18	162
Total	0	0	385	316	36

Variants in CLCN6

This is a list of pathogenic ClinVar variants found in the CLCN6 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-11806126-C-T		Homocystinuria due to methylene tetrahydrofolate reductase deficiency	Benign (Jan 12, 2024)
1-11806266-G-A			Uncertain significance (Jun 19, 2022)
1-11806269-G-A			Uncertain significance (Jan 11, 2024)
1-11806271-G-GTGCAGGGGGTCTCTGTGCTGCTGC			Uncertain significance (Jun 19, 2022)
1-11806275-A-G			Uncertain significance (Mar 22, 2022)
1-11806275-AG-A			Uncertain significance (Sep 12, 2023)
1-11806278-G-A		not specified	Uncertain significance (Dec 12, 2023)
1-11806279-G-A			Uncertain significance (Jul 28, 2023)
1-11806280-G-A			Likely benign (Jan 22, 2024)
1-11806280-G-T			Likely benign (Aug 30, 2021)
1-11806282-C-T			Uncertain significance (Dec 08, 2022)
1-11806284-C-G			Uncertain significance (Feb 01, 2024)
1-11806284-C-T			Likely benign (Oct 22, 2023)
1-11806285-TGTGCTGCTGCTGCAGGTG-T			Uncertain significance (Oct 17, 2022)
1-11806286-G-A			Likely benign (Feb 24, 2023)
1-11806285-T-TGTGCTGCTGCTGCAGGTG			Uncertain significance (Jan 25, 2024)
1-11806286-G-GTGC			Uncertain significance (Apr 02, 2022)
1-11806289-CTGCTGCTGCAGGTGG-C			Uncertain significance (Mar 11, 2023)
1-11806292-C-T			Likely benign (Jan 15, 2024)
1-11806300-G-A			Uncertain significance (Jan 20, 2023)
1-11806304-GTGC-G			Uncertain significance (Aug 28, 2021)
1-11806311-T-A			Uncertain significance (Oct 29, 2023)
1-11806316-C-T			Likely benign (Aug 09, 2022)
1-11806318-G-C			Uncertain significance (Mar 17, 2022)
1-11806318-G-T			Uncertain significance (Dec 20, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN6	protein_coding	protein_coding	ENST00000346436	23	36995

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.11e-8	1.00	125705	0	43	125748	0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.59	439	543	0.808	0.0000340	5680
Missense in Polyphen		152	209.13	0.72684		2094
Synonymous	-0.895	239	222	1.08	0.0000151	1733
Loss of Function	3.78	21	49.7	0.422	0.00000270	531

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000386	0.000385
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000185	0.000185
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000984	0.0000980
Other	0.000655	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Chloride transport protein, initially identified as voltage-gated chloride channel. The presence of the conserved gating glutamate residues suggests that is functions as antiporter.
• Pathway: Disease;Stimuli-sensing channels;Ion channel transport;Transport of small molecules;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction (Consensus)

Recessive Scores

• pRec: 0.196

Intolerance Scores

• loftool: 0.0974
• rvis_EVS: -1.57
• rvis_percentile_EVS: 3.17

Haploinsufficiency Scores

• pHI: 0.439
• hipred: Y
• hipred_score: 0.575
• ghis: 0.613

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.964

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clcn6
• Phenotype: cellular 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); 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)

Gene ontology

• Biological process: chloride transport;cell volume homeostasis;signal transduction;response to mechanical stimulus;ion transmembrane transport;chloride transmembrane transport
• Cellular component: lysosomal membrane;endosome membrane;integral component of membrane
• Molecular function: voltage-gated chloride channel activity;protein binding;ATP binding;antiporter activity