LRRC8C

protein-coding

leucine rich repeat containing 8 VRAC subunit C, the group of Volume regulated anion channel subunits

Gene summary

Enables volume-sensitive anion channel activity. Involved in cyclic-GMP-AMP transmembrane import across plasma membrane and monoatomic anion transmembrane transport. Located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_032270.5

Inheritance

ClinVar variants

P:2U:71B:4

Top phenotype

Telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature (TIMES syndrome)

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr1:89,633,072-89,769,903

External References & Databases

Ensembl (ENSG00000171488)

Transcript & Mutation Effects

hg38 • Region Span ~136.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short statureMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0975957

Submitter: PanelApp Australia

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature (TIMES syndrome)AD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Hematologic

Rationale: Individuals may be affected by telangiectasia involving the gastrointestinal tract, resulting in hemorrhage that has been described as requiring RBC transfusion, and awareness may allow prompt management

Refs: 39623139

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LRRC8C variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 66

not providedTotal: 6

LRRC8C-related conditionTotal: 4

Telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short statureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032270.5. 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				1 clinvar	1 clinvar	2
missense	1 clinvar		69 clinvar	1 clinvar	1 clinvar	72
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	2	0	71	2	2	77

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032270.5	RefSeq	NP_115646.3	2	MANE Select
ENST00000370454.9	Ensembl	ENSP00000359483.4	2	MANE Select
ENST00000482063.1	Ensembl	ENSP00000436638.1	2	Standard
ENST00000856739.1	Ensembl	ENSP00000526798.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transport of small molecules
Miscellaneous transport and binding events

Biological Process

cell volume homeostasis
inorganic anion transport
taurine transport
aspartate transmembrane transport
protein hexamerization

Molecular Function

volume-sensitive anion channel activity
protein binding

Cellular Component

cytoplasm
endoplasmic reticulum membrane
plasma membrane
integral component of plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370454
Coding exons: 2
Length: 136832
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125747
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.58	277	427	0.649	0.0000223	5324
Missense (PolyPhen)		65	168.37	0.38604		2225
Synonymous	0.823	154	168	0.919	0.00000863	1572
Loss of Function	2.97	10	26.5	0.377	0.00000168	308

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress. Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. {ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:26824658, ECO:0000269|PubMed:28193731}.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.642
RVIS EVS: 0.09
RVIS percentile EVS: 60.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.147

Gene Damage Prediction

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