LRRC8A

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

Basic information

Region (hg38): 9:128882133-128918039

Previous symbols: [ "LRRC8" ]

Links

ENSG00000136802 ∙ NCBI:56262 ∙ OMIM:608360 ∙ HGNC:19027 ∙ Uniprot:Q8IWT6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal agammaglobulinemia (Supportive), mode of inheritance: AD
• agammaglobulinemia 5, autosomal dominant (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Agammaglobulinemia 5	AD	Allergy/Immunology/Infectious	Congenital agammaglobulinemia has been described, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious	14660746
Only one individual (with a translocation affecting LRRC8A) has been described; This individual also demonstrated dysmorphic facies in addition to agammaglobulinemia

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRRC8A gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRRC8A 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				163	18	181
missense			186	2		188
nonsense						0
start loss						0
frameshift			3			3
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding				3	4	7
Total	0	0	191	168	22

Variants in LRRC8A

This is a list of pathogenic ClinVar variants found in the LRRC8A region.

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

Position	Type	Phenotype	Significance	ClinVar
9-128907146-C-T			Benign (Jun 09, 2021)
9-128907163-C-T		Agammaglobulinemia 5, autosomal dominant • LRRC8A-related disorder	Benign (Sep 22, 2023)
9-128907173-G-A			Likely benign (Jun 09, 2023)
9-128907187-G-A			Uncertain significance (Nov 30, 2022)
9-128907197-G-A		Agammaglobulinemia 5, autosomal dominant	Likely benign (Jan 11, 2024)
9-128907202-C-T			Uncertain significance (Sep 23, 2023)
9-128907203-G-A			Likely benign (Oct 04, 2023)
9-128907208-C-T			Uncertain significance (Dec 25, 2023)
9-128907212-A-G			Likely benign (Oct 24, 2021)
9-128907215-C-T		Agammaglobulinemia 5, autosomal dominant • LRRC8A-related disorder	Benign (Jan 12, 2024)
9-128907230-G-A			Likely benign (Dec 12, 2023)
9-128907249-GACT-G			Uncertain significance (Nov 28, 2022)
9-128907263-C-T			Likely benign (Sep 27, 2021)
9-128907264-G-A		not specified	Uncertain significance (Apr 27, 2023)
9-128907267-A-G			Uncertain significance (Dec 10, 2020)
9-128907268-T-A			Uncertain significance (Mar 23, 2023)
9-128907281-C-T		LRRC8A-related disorder	Benign (Jan 29, 2024)
9-128907284-C-T			Likely benign (Apr 24, 2023)
9-128907287-C-T			Benign (Jan 06, 2024)
9-128907290-G-A			Likely benign (Jul 29, 2022)
9-128907296-G-A			Likely benign (Feb 26, 2023)
9-128907308-C-T			Likely benign (Sep 06, 2022)
9-128907338-G-A			Likely benign (Sep 09, 2022)
9-128907353-C-T			Likely benign (Jun 13, 2022)
9-128907363-G-T		not specified	Uncertain significance (Feb 16, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRRC8A	protein_coding	protein_coding	ENST00000259324	2	35928

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.944	0.0560	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.38	303	519	0.583	0.0000379	5295
Missense in Polyphen		125	271.11	0.46107		3002
Synonymous	-0.816	263	247	1.07	0.0000186	1667
Loss of Function	3.79	3	22.3	0.134	0.00000106	266

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000617	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000653	0.0000653
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: 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 (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:29769723). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731). Can form functional channels by itself (in vitro) (PubMed:26824658). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746). Also required for T-cell development (By similarity). {ECO:0000250|UniProtKB:Q80WG5, ECO:0000269|PubMed:14660746, ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:26530471, ECO:0000269|PubMed:26824658, ECO:0000269|PubMed:28193731, ECO:0000269|PubMed:29769723}.
• Disease: DISEASE: Agammaglobulinemia 5, autosomal dominant (AGM5) [MIM:613506]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. {ECO:0000269|PubMed:14660746}. Note=The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains.
• Pathway: miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Transport of small molecules;Miscellaneous transport and binding events (Consensus)

Recessive Scores

• pRec: 0.118

Intolerance Scores

• loftool: 0.0656
• rvis_EVS: -1.57
• rvis_percentile_EVS: 3.16

Haploinsufficiency Scores

• pHI: 0.271
• hipred: Y
• hipred_score: 0.562
• ghis: 0.598

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.780

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lrrc8a
• Phenotype: renal/urinary system phenotype; immune system phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; muscle phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: lrrc8aa
• Affected structure: trunk
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: pre-B cell differentiation;anion transport;cell volume homeostasis;response to osmotic stress;inorganic anion transport;taurine transport;aspartate transmembrane transport;protein hexamerization;transmembrane transport;anion transmembrane transport
• Cellular component: cytoplasm;plasma membrane;integral component of plasma membrane;cell surface;membrane;ion channel complex
• Molecular function: volume-sensitive anion channel activity;anion channel activity;protein binding;identical protein binding