CLIC5

protein-coding

chloride intracellular channel 5, the group of Chloride intracellular channels

Gene summary

This gene encodes a member of the chloride intracellular channel (CLIC) family of chloride ion channels. The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation and glomerular podocyte and endothelial cell maintenance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

MANE transcript

NM_016929.5

Inheritance

ClinVar variants

P:3U:69B:42

Top phenotype

Deafness, autosomal recessive 103

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr6:45,880,827-46,080,348

External References & Databases

Ensembl (ENSG00000112782)

Transcript & Mutation Effects

hg38 • Region Span ~199.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 103LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014469

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 103LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014469

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 103AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 24781754

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLIC5 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 103

not specifiedTotal: 58

CLIC5-related disorderTotal: 22

Autosomal recessive nonsyndromic hearing loss 103Total: 5

Hearing loss, autosomal recessiveTotal: 1

Hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016929.5. 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				28 clinvar		28
missense			66 clinvar	14 clinvar		80
nonsense	1 clinvar	1 clinvar	1 clinvar			3
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	1	69	42	0	114

Highest pathogenic variant AF is 0.0000012402701

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016929.5	RefSeq	NP_058625.2	6	MANE Select
ENST00000339561.12	Ensembl	ENSP00000344165.6	6	MANE Select
NM_001114086.2	RefSeq	NP_001107558.1	6	Standard
NM_001256023.2	RefSeq	NP_001242952.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chloride transport
female pregnancy
sensory perception of sound
regulation of ion transmembrane transport
chloride transmembrane transport

Molecular Function

voltage-gated ion channel activity
chloride channel activity
protein binding

Cellular Component

Golgi apparatus
microtubule organizing center
cell cortex
actin cytoskeleton
chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000185206
Coding exons: 6
Length: 180088
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125745
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.539	209	232	0.900	0.0000129	2694
Missense (PolyPhen)		76	84.121	0.90346		918
Synonymous	-0.567	107	99.8	1.07	0.00000609	777
Loss of Function	1.06	11	15.5	0.710	6.48e-7	221

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000081	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal hearing (PubMed:24781754). It is necessary for the formation of stereocilia in the inner ear and normal development of the organ of Corti (By similarity). Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. May play a role in the regulation of transepithelial ion absorption and secretion. Is required for the development and/or maintenance of the proper glomerular endothelial cell and podocyte architecture (PubMed:15184393, PubMed:18028448, PubMed:20335315). {ECO:0000250|UniProtKB:Q8BXK9, ECO:0000269|PubMed:15184393, ECO:0000269|PubMed:18028448, ECO:0000269|PubMed:20335315, ECO:0000269|PubMed:24781754}.;
Disease: DISEASE: Deafness, autosomal recessive, 103 (DFNB103) [MIM:616042]: A form of sensorineural deafness with onset in early childhood. Hearing impairment progresses from mild to severe or even profound before the second decade, and is accompanied by vestibular areflexia. {ECO:0000269|PubMed:24781754}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0942

Intolerance Scores

LoFtool: 0.153
RVIS EVS: 1.02
RVIS percentile EVS: 90.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.457

Gene Damage Prediction

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