CLIC2

protein-coding

chloride intracellular channel 2, the group of Chloride intracellular channels

Gene summary

This gene encodes a chloride intracellular channel protein. 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. This protein plays a role in inhibiting the function of ryanodine receptor 2. A mutation in this gene is the cause of an X-linked form of cognitive disability. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001289.6

Inheritance

ClinVar variants

U:65B:13

Top phenotype

Intellectual developmental disorder, X-linked, syndromic 32

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chrX:155,276,211-155,334,657

External References & Databases

Ensembl (ENSG00000155962)

Transcript & Mutation Effects

hg38 • Region Span ~58.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic 32LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010473

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic 32LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010473

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic 32MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010473

Submitter: Genomics England PanelApp

X-linked complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

CLIC2 was first reported in relation to X-linked complex neurodevelopmental disorder in 2012 by Takano et al., PMID: 22814392. The three individuals (from two unrelated families) reported to date in the literature with variants in this gene had phenotypes including intellectual disability, delayed psychomotor development, seizures, and adult onset cardiac issues such as congestive heart failure, valvular insufficiency, atrial fibrillation, and cardiomegaly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of the reported disease entities, including syndromic X-linked mental retardation-32 (OMIM # 300886) and X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome (ORPHA:324410, MONDO:0010473) have been lumped into one disease entity: X-linked complex neurodevelopmental disorder. Although two unique variants (both missense) have been reported in humans, the first published variant (Takano et al., PMID: 22814392) has been ruled out from disease-causality based on the presence of this variant in adult males in the (non-neuro) gnomAD population database (v.2.1.1). Given the dearth of experimental evidence linking CLIC2 with disease, and the scarcity of plausible reports of disease-causing variants in humans, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for the second published variant, a missense change with no supportive functional data (Vissers et al., PMID: 28333917). In summary, there is disputed evidence supporting the relationship between CLIC2 and X-linked complex neurodevelopmental disorder. More evidence is needed to either support or refute the role CLIC2 plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 2/16/2021 (SOP Version 8).

intellectual developmental disorder, X-linked, syndromic 32SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010473

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic 32NO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0010473

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic 32XL

Manifestation: Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Among other manifestations, individuals have been described as including cardiac findings such as atrial fibrillation, congestive heart failure, valvular insufficiency, and awareness may allow surveillance and early medical management

Refs: 22814392

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLIC2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 36

not providedTotal: 14

X-linked intellectual disability-cardiomegaly-congestive heart failure syndromeTotal: 6

CLIC2-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001289.6. 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			6 clinvar	7 clinvar		13
missense			44 clinvar	6 clinvar		50
nonsense			3 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			12 clinvar			12
Total	0	0	65	13	0	78

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001289.6	RefSeq	NP_001280.3	6	MANE Select
ENST00000369449.7	Ensembl	ENSP00000358460.2	6	MANE Select
ENST00000321926.4	Ensembl	ENSP00000318558.4	4	Standard
ENST00000948941.1	Ensembl	ENSP00000619000.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pantoprazole Action Pathway
Rabeprazole Action Pathway
Esomeprazole Action Pathway
Omeprazole Action Pathway
Lansoprazole Action Pathway

Biological Process

signal transduction
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion
positive regulation of binding
negative regulation of ryanodine-sensitive calcium-release channel activity

Molecular Function

glutathione transferase activity
glutathione peroxidase activity
voltage-gated ion channel activity
chloride channel activity
protein binding

Cellular Component

nucleus
cytoplasm
chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369449
Coding exons: 6
Length: 58467
Individuals with no LoFs: 125735
Homozygous LoFs: 1
Heterozygous LoFs: 3
Defined: 125739
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.27	58	92.4	0.628	0.00000699	1632
Missense (PolyPhen)		14	41.398	0.33818		721
Synonymous	0.118	33	33.9	0.974	0.00000249	455
Loss of Function	1.43	3	7.13	0.421	4.46e-7	152

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000025	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Modulates the activity of RYR2 and inhibits calcium influx. {ECO:0000269|PubMed:15147738, ECO:0000269|PubMed:15916532, ECO:0000269|PubMed:17945253}.;
Disease: DISEASE: Mental retardation, X-linked, syndromic, 32 (MRXS32) [MIM:300886]: A mental retardation syndrome characterized by profound intellectual deficit, delayed psychomotor development beginning in infancy and little or no speech development. Additional features include seizures, large joint contractures, and abnormal positioning of the thumbs. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:22814392}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.140

Intolerance Scores

LoFtool: 0.140
RVIS EVS: 0.19
RVIS percentile EVS: 66.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.903

Gene Damage Prediction

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