SCNN1A

sodium channel epithelial 1 subunit alpha, the group of Sodium channels epithelial

Basic information

Region (hg38): 12:6346843-6377730

Previous symbols: [ "SCNN1" ]

Links

ENSG00000111319 ∙ ∙ OMIM:600228 ∙ HGNC:10599 ∙ Uniprot:P37088 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• bronchiectasis with or without elevated sweat chloride 2 (Strong), mode of inheritance: AD
• pseudohypoaldosteronism, type IB1, autosomal recessive (Strong), mode of inheritance: AR
• Liddle syndrome (Supportive), mode of inheritance: AD
• Brugada syndrome (Supportive), mode of inheritance: AD
• pseudohypoaldosteronism, type IB1, autosomal recessive (Supportive), mode of inheritance: AR
• pseudohypoaldosteronism, type IB1, autosomal recessive (Definitive), mode of inheritance: AR
• bronchiectasis with or without elevated sweat chloride 2 (Moderate), mode of inheritance: AD
• pseudohypoaldosteronism, type IB1, autosomal recessive (Strong), mode of inheritance: AR
• Liddle syndrome 3 (Limited), mode of inheritance: AD
• bronchiectasis with or without elevated sweat chloride 2 (Limited), mode of inheritance: Unknown
• Liddle syndrome 3 (Limited), mode of inheritance: Unknown
• pseudohypoaldosteronism, type IB1, autosomal recessive (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoaldosteronism, type IB1; Liddle syndrome 3; Bronchiectasis with or without elevated sweat chloride 2	AD/AR/Digenic (with CFTR or other SCCN1 genes)	Allergy/Immunology/Infectious; Pulmonary; Renal	In Pseudohypoaldosteronism, type 1B1, treatment with electrolyte replacement and control of hyperkalemia can be effective; In Liddle syndrome, certain medications (eg, amiloride, triamterene, but not spironolactone) and dietary sodium restriction can effectively treat hypertension and hypokalemia; In Bronchiectasis with or without elevated sweat chloride 2, as in cystic fibrosis, early and aggressive pulmonary and other management (eg, related to prophylaxis and management of respiratory infections) may decrease morbidity	Allergy/Immunology/Infectious; Pulmonary; Renal	8589714; 9654209; 10202170; 9462466; 19017867

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCNN1A gene.

• Pseudohypoaldosteronism,_type_IB1,_autosomal_recessive (182 variants)
• Bronchiectasis_with_or_without_elevated_sweat_chloride_2 (175 variants)
• not_provided (141 variants)
• Liddle_syndrome_3 (136 variants)
• Inborn_genetic_diseases (87 variants)
• not_specified (12 variants)
• SCNN1A-related_disorder (11 variants)
• Incidental_Discovery (1 variants)
• Idiopathic_bronchiectasis (1 variants)
• Neurodevelopmental_delay (1 variants)
• Prostate_cancer (1 variants)
• Brugada_syndrome_1 (1 variants)
• Pseudohypoaldosteronism (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCNN1A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000001038.6. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	38	1	49
missense	1	4	184	24	1	214
nonsense	2	2	1	1		6
start loss			1			1
frameshift	10	6	1	1		18
splice donor/acceptor (+/-2bp)	3	5	1	1		10
Total	16	17	198	65	2

Highest pathogenic variant AF is 0.000122722

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCNN1A	protein_coding	protein_coding	ENST00000360168	12	30888

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.08e-11	0.908	125626	0	122	125748	0.000485

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.490	443	415	1.07	0.0000243	4728
Missense in Polyphen		146	151.71	0.96236		1768
Synonymous	-0.405	182	175	1.04	0.0000107	1457
Loss of Function	1.97	23	35.7	0.644	0.00000222	362

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000656	0.000656
Ashkenazi Jewish	0.000695	0.000695
East Asian	0.00136	0.00136
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000547	0.000510
Middle Eastern	0.00136	0.00136
South Asian	0.000295	0.000294
Other	0.000498	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception. {ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:8278374}.
• Disease: DISEASE: Pseudohypoaldosteronism 1, autosomal recessive (PHA1B) [MIM:264350]: A rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1B is a severe form involving multiple organ systems, and characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and weight loss. {ECO:0000269|PubMed:10586178, ECO:0000269|PubMed:15853823, ECO:0000269|PubMed:18634878}. Note=The disease is caused by mutations affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878). {ECO:0000269|PubMed:18634878}.; DISEASE: Bronchiectasis with or without elevated sweat chloride 2 (BESC2) [MIM:613021]: A debilitating respiratory disease characterized by chronic, abnormal dilatation of the bronchi and other cystic fibrosis-like symptoms in the absence of known causes of bronchiectasis (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common variable immunodeficiency, foreign body obstruction). Clinical features include sub-normal lung function, sinopulmonary infections, chronic productive cough, excessive sputum production, and elevated sweat chloride in some cases. {ECO:0000269|PubMed:19462466}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aldosterone-regulated sodium reabsorption - Homo sapiens (human);Taste transduction - Homo sapiens (human);Diuretics Pathway, Pharmacodynamics;Polythiazide Action Pathway;Methyclothiazide Action Pathway;Bumetanide Action Pathway;Spironolactone Action Pathway;Eplerenone Action Pathway;Triamterene Action Pathway;Amiloride Action Pathway;Ethacrynic Acid Action Pathway;Quinethazone Action Pathway;Bendroflumethiazide Action Pathway;Chlorthalidone Action Pathway;Trichlormethiazide Action Pathway;Iminoglycinuria;Lysinuric Protein Intolerance;Blue diaper syndrome;Lysinuric protein intolerance (LPI);Cystinuria;Indapamide Action Pathway;Furosemide Action Pathway;Torsemide Action Pathway;Hartnup Disorder;Glucose Transporter Defect (SGLT2);Kidney Function;Glucose Transporter Defect (SGLT2);Metolazone Action Pathway;Hydrochlorothiazide Action Pathway;Cyclothiazide Action Pathway;Hydroflumethiazide Action Pathway;Chlorothiazide Action Pathway;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.290

Intolerance Scores

• loftool: 0.952
• rvis_EVS: 0.27
• rvis_percentile_EVS: 70.64

Haploinsufficiency Scores

• pHI: 0.970
• hipred: Y
• hipred_score: 0.595
• ghis: 0.567

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.644

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Scnn1a
• Phenotype: respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); normal phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: sodium ion transmembrane transport;multicellular organismal water homeostasis;response to stimulus;sensory perception of taste;sodium ion homeostasis
• Cellular component: acrosomal vesicle;cytoplasm;plasma membrane;integral component of plasma membrane;apical plasma membrane;motile cilium;sodium channel complex;ciliary membrane;extracellular exosome;sperm principal piece
• Molecular function: protein binding;ligand-gated sodium channel activity;WW domain binding