CLCN4

chloride voltage-gated channel 4, the group of Chloride voltage-gated channels

Basic information

Region (hg38): X:10156974-10237660

Links

ENSG00000073464 ∙ NCBI:1183 ∙ OMIM:302910 ∙ HGNC:2022 ∙ Uniprot:P51793 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• intellectual disability, X-linked 49 (Strong), mode of inheritance: XL
• intellectual disability, X-linked 49 (Strong), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Raynaud-Claes syndrome	XL	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	8826458; 9415477; 23647072; 25644381

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN4 gene.

• not provided (471 variants)
• Intellectual disability, X-linked 49 (66 variants)
• not specified (13 variants)
• Inborn genetic diseases (12 variants)
• CLCN4-related disorder (11 variants)
• CLCN4-related condition (4 variants)
• Intellectual disability (3 variants)
• Neurodevelopmental disorder (2 variants)
• See cases (2 variants)
• Global developmental delay (1 variants)
• Seizure (1 variants)
• Microcephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN4 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			3	118	30	151
missense	7	12	198	9	10	236
nonsense	4					4
start loss		1				1
frameshift	4	4				8
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	1				2
splice region			8	19	2	29
non coding			2	43	34	79
Total	16	18	204	170	74

Variants in CLCN4

This is a list of pathogenic ClinVar variants found in the CLCN4 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-10158556-G-T			Uncertain significance (Jun 11, 2018)
X-10185033-A-G			Likely pathogenic (Feb 06, 2023)
X-10185042-G-T		Intellectual disability, X-linked 49	Uncertain significance (Mar 30, 2021)
X-10185043-C-T		Intellectual disability, X-linked 49	Uncertain significance (Aug 04, 2023)
X-10185044-G-A			Likely benign (May 02, 2018)
X-10185048-G-A			Uncertain significance (Mar 23, 2018)
X-10185049-C-T			Uncertain significance (Apr 07, 2023)
X-10185050-G-A			Likely benign (Feb 06, 2022)
X-10185053-G-A			Uncertain significance (Jul 06, 2022)
X-10185069-C-A			Uncertain significance (Jul 28, 2023)
X-10185070-TGATGGATTTCCTC-T		Intellectual disability, X-linked 49	Pathogenic (Nov 07, 2018)
X-10185074-G-T			Uncertain significance (Jul 16, 2023)
X-10185075-G-A		CLCN4-related disorder	Conflicting classifications of pathogenicity (Mar 22, 2016)
X-10185076-A-T			Likely benign (Dec 04, 2019)
X-10185083-C-G			Likely benign (Jan 22, 2024)
X-10185083-C-T			Benign (Jan 05, 2024)
X-10185091-C-A			Uncertain significance (Apr 01, 2019)
X-10185091-C-T			Uncertain significance (May 20, 2023)
X-10185092-G-A			Likely benign (Jun 10, 2023)
X-10185096-C-G			Uncertain significance (Nov 01, 2022)
X-10185104-G-A			Likely benign (Nov 06, 2023)
X-10185110-G-A			Benign (Jan 24, 2024)
X-10185119-C-G		Intellectual disability, X-linked 49	Uncertain significance (May 27, 2022)
X-10185132-G-A		Intellectual disability, X-linked 49	Uncertain significance (May 27, 2022)
X-10185140-A-G			Likely benign (Jun 27, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN4	protein_coding	protein_coding	ENST00000380833	11	80677

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.00107	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.52	112	350	0.320	0.0000306	4971
Missense in Polyphen		20	123	0.1626		1796
Synonymous	0.0404	155	156	0.996	0.0000149	1557
Loss of Function	4.13	0	19.8	0.00	0.00000126	353

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: Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. {ECO:0000269|PubMed:23647072, ECO:0000269|PubMed:25644381}.
• Pathway: Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.183

Intolerance Scores

• rvis_EVS: -1.09
• rvis_percentile_EVS: 7.05

Haploinsufficiency Scores

• pHI: 0.320
• hipred: Y
• hipred_score: 0.728
• ghis: 0.585

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.307

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clcn4
• Phenotype: homeostasis/metabolism phenotype; renal/urinary system phenotype

Gene ontology

• Biological process: chloride transport;ion transmembrane transport;chloride transmembrane transport;proton transmembrane transport
• Cellular component: endosome;early endosome;endoplasmic reticulum membrane;Golgi apparatus;plasma membrane;integral component of plasma membrane;endosome membrane;early endosome membrane;late endosome membrane
• Molecular function: voltage-gated chloride channel activity;chloride channel activity;ATP binding;antiporter activity;solute:proton antiporter activity;chloride ion binding