Bronchiectasis with or without elevated sweat chloride 3

Summary

Bronchiectasis with or without elevated sweat chloride 3 (MONDO:0013112) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 118

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bronchiectasis with or without elevated sweat chloride 3
Mondo ID	MONDO:0013112
MeSH	C567772
OMIM	613071
DOID	DOID:0080528
UMLS	C2751324
MedGen	414351
GARD	0018056
Is cancer (heuristic)	no

Also known as: BESC3 · bronchiectasis caused by mutation in SCNN1G · bronchiectasis with or without elevated sweat chloride 3 · bronchiectasis with or without elevated sweat chloride type 3 · SCNN1G bronchiectasis

Data availability: 118 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › bronchial disorder › bronchiectasis › idiopathic bronchiectasis › bronchiectasis with or without elevated sweat chloride 3

Related subtypes (2): bronchiectasis with or without elevated sweat chloride 1, bronchiectasis with or without elevated sweat chloride 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

118 retrieved; paginated sample, class counts are floors:

97 uncertain significance, 6 benign, 5 benign/likely benign, 5 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323567	NM_001039.4(SCNN1G):c.412C>T (p.Arg138Ter)	SCNN1G	Pathogenic	criteria provided, multiple submitters, no conflicts
3579896	NM_001039.4(SCNN1G):c.416_417del (p.Glu139fs)	SCNN1G	Likely pathogenic	criteria provided, single submitter
804476	NM_001039.4(SCNN1G):c.142dup (p.Arg48fs)	SCNN1G	Likely pathogenic	criteria provided, single submitter
2883968	NM_001039.4(SCNN1G):c.1550T>A (p.Met517Lys)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318350	NM_001039.4(SCNN1G):c.538C>T (p.Arg180Trp)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318359	NM_001039.4(SCNN1G):c.1589A>G (p.Asn530Ser)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318360	NM_001039.4(SCNN1G):c.1827G>C (p.Leu609Phe)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451433	NM_001039.4(SCNN1G):c.1550T>C (p.Met517Thr)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034392	NM_001039.4(SCNN1G):c.1284C>T (p.His428=)	SCNN1G	Uncertain significance	criteria provided, single submitter
1065571	NM_001039.4(SCNN1G):c.1654G>A (p.Val552Ile)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1184406	NM_001039.4(SCNN1G):c.1400G>A (p.Ser467Asn)	SCNN1G	Uncertain significance	criteria provided, single submitter
1185021	NM_001039.4(SCNN1G):c.1532T>A (p.Leu511Gln)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1304028	NM_001039.4(SCNN1G):c.1874C>G (p.Pro625Arg)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1313539	NM_001039.4(SCNN1G):c.470G>A (p.Arg157Gln)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1331727	NM_001039.4(SCNN1G):c.564C>A (p.His188Gln)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2068785	NM_001039.4(SCNN1G):c.835A>T (p.Met279Leu)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2074030	NM_001039.4(SCNN1G):c.436G>A (p.Val146Ile)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2075492	NM_001039.4(SCNN1G):c.1779_1781dup (p.Pro594_Ala595insPro)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2184220	NM_001039.4(SCNN1G):c.1868C>T (p.Pro623Leu)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435777	NM_001039.4(SCNN1G):c.1082A>T (p.Glu361Val)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435778	NM_001039.4(SCNN1G):c.1808C>G (p.Pro603Arg)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2443054	NM_001039.4(SCNN1G):c.201C>G (p.Ile67Met)	SCNN1G	Uncertain significance	criteria provided, single submitter
2514019	NM_001039.4(SCNN1G):c.1465G>C (p.Gly489Arg)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2549831	NM_001039.4(SCNN1G):c.326C>G (p.Thr109Ser)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2556560	NM_001039.4(SCNN1G):c.1576A>T (p.Met526Leu)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2610511	NM_001039.4(SCNN1G):c.1131T>G (p.Ser377Arg)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2631991	NM_001039.4(SCNN1G):c.1072C>T (p.His358Tyr)	SCNN1G	Uncertain significance	criteria provided, single submitter
2633627	NM_001039.4(SCNN1G):c.1874C>T (p.Pro625Leu)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2731600	NM_001039.4(SCNN1G):c.551G>T (p.Gly184Val)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
2732418	NM_001039.4(SCNN1G):c.410G>A (p.Arg137His)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCNN1G	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1G	Orphanet:526	Liddle syndrome
SCNN1G	Orphanet:60033	Idiopathic bronchiectasis
SLC4A1	Orphanet:3202	Dehydrated hereditary stomatocytosis
SLC4A1	Orphanet:398088	Hereditary cryohydrocytosis with normal stomatin
SLC4A1	Orphanet:822	Hereditary spherocytosis
SLC4A1	Orphanet:93608	Autosomal dominant distal renal tubular acidosis
SLC4A1	Orphanet:93610	Distal renal tubular acidosis with anemia
SLC4A1	Orphanet:98868	Southeast Asian ovalocytosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCNN1G	HGNC:10602	ENSG00000166828	P51170	Epithelial sodium channel subunit gamma	clinvar
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCNN1G	Epithelial sodium channel subunit gamma	This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis.
SLC4A1	Band 3 anion transport protein	Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCNN1G	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
kidney epithelium	1
renal medulla	1
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCNN1G	133	broad	marker	renal medulla, kidney epithelium, bronchial epithelial cell
SLC4A1	161	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC4A1	1,598
SCNN1G	1,037

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A1	P02730	54
SCNN1G	P51170	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	5710.0×	0.003	SLC4A1
Sensory perception of salty taste	1	951.7×	0.005	SCNN1G
Erythrocytes take up oxygen and release carbon dioxide	1	634.4×	0.005	SLC4A1
O2/CO2 exchange in erythrocytes	1	634.4×	0.005	SLC4A1
Bicarbonate transporters	1	571.0×	0.005	SLC4A1
Transport of small molecules	2	25.1×	0.005	SCNN1G, SLC4A1
Erythrocytes take up carbon dioxide and release oxygen	1	439.2×	0.005	SLC4A1
Sensory perception of taste	1	167.9×	0.012	SCNN1G
SLC transporter disorders	1	102.0×	0.017	SLC4A1
Disorders of transmembrane transporters	1	69.6×	0.020	SLC4A1
Stimuli-sensing channels	1	68.0×	0.020	SCNN1G
R-HSA-425393	1	64.9×	0.020	SLC4A1
Ion channel transport	1	48.0×	0.024	SCNN1G
Sensory Perception	1	47.6×	0.024	SCNN1G
SLC-mediated transmembrane transport	1	29.6×	0.036	SLC4A1
Disease	1	6.5×	0.147	SLC4A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to increased oxygen levels	1	8426.0×	0.002	SLC4A1
pH elevation	1	8426.0×	0.002	SLC4A1
intracellular monoatomic ion homeostasis	1	2106.5×	0.002	SLC4A1
negative regulation of urine volume	1	2106.5×	0.002	SLC4A1
sensory perception of salty taste	1	2106.5×	0.002	SCNN1G
negative regulation of glycolytic process through fructose-6-phosphate	1	1404.3×	0.003	SLC4A1
cellular response to aldosterone	1	1203.7×	0.003	SCNN1G
cellular response to vasopressin	1	1053.2×	0.003	SCNN1G
multicellular organismal-level water homeostasis	1	842.6×	0.003	SCNN1G
sensory perception of sour taste	1	842.6×	0.003	SCNN1G
plasma membrane phospholipid scrambling	1	766.0×	0.003	SLC4A1
monoatomic anion transport	1	702.2×	0.003	SLC4A1
sodium ion homeostasis	1	468.1×	0.004	SCNN1G
bicarbonate transport	1	401.2×	0.004	SLC4A1
intracellular sodium ion homeostasis	1	383.0×	0.004	SCNN1G
cellular response to acidic pH	1	366.4×	0.004	SCNN1G
sodium ion import across plasma membrane	1	312.1×	0.005	SCNN1G
regulation of intracellular pH	1	300.9×	0.005	SLC4A1
erythrocyte development	1	263.3×	0.005	SLC4A1
chloride transport	1	227.7×	0.006	SLC4A1
chloride transmembrane transport	1	118.7×	0.010	SLC4A1
regulation of blood pressure	1	110.9×	0.011	SCNN1G
sodium ion transmembrane transport	1	101.5×	0.011	SCNN1G
blood coagulation	1	86.9×	0.012	SLC4A1
transmembrane transport	1	84.3×	0.012	SLC4A1
protein localization to plasma membrane	1	54.4×	0.018	SLC4A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCNN1G	0	0
SLC4A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SCNN1G	5	Binding:3, ADMET:1, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SCNN1G, SLC4A1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SCNN1G	5	—
SLC4A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.