BSND

protein-coding

barttin CLCNK type accessory subunit beta, the group of Chloride voltage-gated channels

Gene summary

This gene encodes an essential beta subunit for CLC chloride channels. These heteromeric channels localize to basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear. Mutations in this gene have been associated with Bartter syndrome with sensorineural deafness. [provided by RefSeq, Jul 2008]

Previous symbols:

DFNB73

MANE transcript

NM_057176.3

Inheritance

ClinVar variants

P:44U:124B:173

Top phenotype

Bartter syndrome, type 4A, neonatal, with sensorineural deafness

gnomAD constraint

pLI —, LoF o/e 1.19

Max pathogenic AF

—

Genomic locus

chr1:54,998,933-55,017,172

External References & Databases

Ensembl (ENSG00000162399)

Transcript & Mutation Effects

hg38 • Region Span ~18.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bartter disease type 4ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011242

Submitter: Labcorp Genetics (formerly Invitae)

Bartter disease type 4ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011242

Submitter: G2P

Bartter disease type 4ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011242

Submitter: Natera

Bartter disease type 4ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011242

Submitter: ClinGen

The BSND gene has been associated with autosomal recessive Bartter syndrome using the ClinGen Clinical Validity Framework as of 12/20/2016. This association was made using case-level data only). At least 8 missense, start loss, deletion, and frameshift variants have been reported in humans. BSND was first associated with this disease in humans as early as 2001 (Birkenhager et al.). Association is seen in at least 10 probands in 4 publications (11687798, 12574213, 23110775, 16583241). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. Of note, this gene has also been implicated in nonsyndromic hearing loss. Expert review determined there was not enough convincing evidence to split out this disease. This gene-disease association is supported by functional studies that exhibit the molecular basis for disease of these variants (Birkenhager et al. 2001, Waldegger et al. 2002, Janssen et al. 2009) . A BSND mouse models have also been created that exhibit the hearing loss phenotypes seen in Bartter syndrome (Rickheit et al. 2008). In summary, BSND is definitively associated with autosomal recessive Bartter syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 7/10/2018.

Bartter disease type 4ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011242

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Bartter syndrome type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019524

Submitter: Orphanet

Clinical Genomic Database (CGD)

Bartter syndrome, type 4A, neonatal, with sensorineural deafnessAR

Manifestation: Audiologic/Otolaryngologic; Renal

Intervention: Audiologic/Otolaryngologic; Renal

Rationale: Individuals may have renal perturbations, (eg, including metabolic alkalosis and hypokalemia), for which treatment can be beneficial; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 11687798; 12574213; 19646679; 21158220; 21269598; 23110775; 30174009; 31667618

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BSND variants in ClinVar

11 Conditions Cataloged

not providedTotal: 305

Bartter syndromeTotal: 87

Bartter disease type 4ATotal: 70

not specifiedTotal: 51

Inborn genetic diseasesTotal: 47

BSND-related disorderTotal: 28

Sensorineural deafness with mild renal dysfunctionTotal: 2

Hearing loss, autosomal recessiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_057176.3. 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			3 clinvar	153 clinvar	1 clinvar	157
missense	3 clinvar	6 clinvar	112 clinvar	17 clinvar		138
nonsense	5 clinvar	6 clinvar	5 clinvar	1 clinvar		17
start loss	1 clinvar	1 clinvar				2
frameshift	5 clinvar	9 clinvar	4 clinvar	1 clinvar		19
splice donor/acceptor (+/-2bp)	2 clinvar	6 clinvar				8
Total	16	28	124	172	1	341

Highest pathogenic variant AF is 0.0001897232

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_057176.3	RefSeq	NP_476517.1	4	MANE Select
ENST00000651561.1	Ensembl	ENSP00000498282.1	4	MANE Select
ENST00001145122.1	Ensembl	ENSP00000815178.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Diuretics Pathway, Pharmacodynamics
Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

ion transmembrane transport
chloride transmembrane transport

Molecular Function

voltage-gated chloride channel activity
chloride channel activity
chloride channel regulator activity

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
basolateral plasma membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371265
Coding exons: 4
Length: 11951
Individuals with no LoFs: 125660
Homozygous LoFs: 0
Heterozygous LoFs: 88
Defined: 125748
p: 0.000350

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0663	190	193	0.987	0.0000112	2125
Missense (PolyPhen)		72	70.195	1.0257		796
Synonymous	-1.42	96	79.8	1.20	0.00000501	615
Loss of Function	-0.605	14	11.8	1.19	5.06e-7	129

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0021	0.0021	notable
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00049	0.00049	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a beta-subunit for CLCNKA and CLCNKB chloride channels. In the kidney CLCNK/BSND heteromers mediate chloride reabsorption by facilitating its basolateral efflux. In the stria, CLCNK/BSND channels drive potassium secretion by recycling chloride for the basolateral SLC12A2 cotransporter. {ECO:0000269|PubMed:11734858, ECO:0000269|PubMed:12111250}.;
Disease: DISEASE: Bartter syndrome 4A, neonatal, with sensorineural deafness (BARTS4A) [MIM:602522]: A form of Bartter syndrome, an autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. BARTS4A is associated with sensorineural deafness. {ECO:0000269|PubMed:11687798, ECO:0000269|PubMed:12111250, ECO:0000269|PubMed:12574213, ECO:0000269|PubMed:12761627}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.365

Intolerance Scores

LoFtool: 0.323
RVIS EVS: -0.36
RVIS percentile EVS: 29.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0856

Gene Damage Prediction

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