CLIC4

protein-coding

chloride intracellular channel 4, the group of Chloride intracellular channels

Gene summary

Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 4 (CLIC4) protein, encoded by the CLIC4 gene, is a member of the p64 family; the gene is expressed in many tissues and exhibits a intracellular vesicular pattern in Panc-1 cells (pancreatic cancer cells). [provided by RefSeq, Jul 2008]

MANE transcript

NM_013943.3

Inheritance

—

ClinVar variants

P:1U:23

Top phenotype

Short stature

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr1:24,745,382-24,844,321

External References & Databases

Ensembl (ENSG00000169504)

Transcript & Mutation Effects

hg38 • Region Span ~98.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLIC4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 19

Short statureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013943.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous						0
missense		1 clinvar	21 clinvar			22
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	1	23	0	0	24

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013943.3	RefSeq	NP_039234.1	6	MANE Select
ENST00000374379.9	Ensembl	ENSP00000363500.4	6	MANE Select
ENST00000488683.1	Ensembl	ENSP00000436538.1	6	Standard
ENST00000889870.1	Ensembl	ENSP00000559929.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

angiogenesis
endothelial cell morphogenesis
chloride transport
vacuolar acidification
fertilization

Molecular Function

voltage-gated ion channel activity
chloride channel activity
protein binding

Cellular Component

nucleus
cytoplasm
mitochondrion
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374379
Coding exons: 6
Length: 98968
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.792	105	130	0.805	0.00000615	1678
Missense (PolyPhen)		13	26.472	0.49109		329
Synonymous	-0.302	53	50.3	1.05	0.00000252	464
Loss of Function	1.22	6	10.2	0.587	4.27e-7	147

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000061	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.00011	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Promotes cell- surface expression of HRH3. Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical- basolateral membrane polarity during mitosis and cytokinesis. Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis). {ECO:0000269|PubMed:12163372, ECO:0000269|PubMed:14569596, ECO:0000269|PubMed:16176272, ECO:0000269|PubMed:16239224, ECO:0000269|PubMed:18302930, ECO:0000269|PubMed:19247789}.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.340
RVIS EVS: -0.23
RVIS percentile EVS: 36.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

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