1-54999325-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_057176.3(BSND):c.139G>A(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00019 in 1,612,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G47G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

BSND
NM_057176.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 3.61

Publications

22 publications found

Variant links:

Genes affected

BSND (HGNC:16512): (barttin CLCNK type accessory subunit beta) 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]

BSND Gene-Disease associations (from GenCC):

Bartter disease type 4A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia
Bartter syndrome type 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BSND links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a region_of_interest Regulates channel membrane trafficking and ion conductance (size 71) in uniprot entity BSND_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_057176.3

PP5

Variant 1-54999325-G-A is Pathogenic according to our data. Variant chr1-54999325-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BSND	NM_057176.3 link	c.139G>A	p.Gly47Arg	missense_variant	Exon 1 of 4	ENST00000651561.1	NP_476517.1	Q8WZ55Q5VU50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BSND	ENST00000651561.1 link	c.139G>A	p.Gly47Arg	missense_variant	Exon 1 of 4		NM_057176.3	ENSP00000498282.1		Q8WZ55

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000997

AC:

AN:

250814

AF XY:

0.0000959

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1460702

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

145

AN XY:

726448

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33460

American (AMR)

AF:

0.0000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000238

AC:

265

AN:

1111210

Other (OTH)

AF:

0.000182

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41428

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68032

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bartter disease type 4A

Pathogenic:9

Dec 01, 2020

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The BSND c.139G>A (p.Gly47Arg) missense variant alters a single amino acid in exon 1 of 4 of the encoded protein. This variant has been previously reported in the homozygous state in five individuals from two families who were affected with early onset Bartter syndrome and bilateral sensorineural hearing loss (PMID: 16572343). This variant has also been observed in the homozygous state in two individuals with congenital hearing loss and a mild clinical presentation of adult-onset Bartter syndrome (PMID: 12574213; 26537508). Additionally, this variant has been found in the compound heterozygous state with a loss-of-function nonsense variant in an individual with congenital hearing loss and early onset Bartter syndrome that required renal transplantation (PMID: 16328537). Functional studies show the p.Gly47Arg variant impairs ClC-K chloride channel activity (PMID: 11734858; 18776122). This variant is observed in the human population Genome Aggregation Database (gnomAD) with a minor allele frequency of 0.01% (25/250,814 alleles, 0 homozygotes) in all populations. In summary, the BSND p.Gly47Arg variant is considered pathogenic. -

Jun 16, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of literature, the BSND c.139G>A (p.Gly47Arg) missense variant has been reported in at least six studies in which it is found in at least twelve individuals from seven families with Bartter syndrome including in eleven in a homozygous state and in one in a compound heterozygous state (Miyamura et al. 2003; Garcia-Nieto et al. 2006; Kitanaka et al. 2006; Brum et al. 2007; Park et al. 2011; Heilberg et al. 2015). The p.Gly47Arg variant was also found in a heterozygous state in at least six unaffected relatives (Garcia-Nieto et al. 2006; Park et al. 2011). The p.Gly47Arg variant was absent from control 100 healthy subjects and is reported at a frequency of 0.000289 in the total population of the Exome Sequencing Project. Expression in Xenopus oocytes demonstrated that the p.Gly47Arg abolished the stimulatory effect on chloride channels (Estevez et al. 2001). The p.Gly47Arg variant demonstrated reduced binding to CIC-K channels when expressed in MDCKII cells (Janssen et al. 2009). These results are consistent with the generally mild phenotype of individuals carrying the p.Gly47Arg variant. Based on the collective evidence, the p.Gly47Arg variant is classified as pathogenic for Bartter syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2025

Laboratory of Molecular Genetics, CHU Rennes

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the BSND protein (p.Gly47Arg). This variant is present in population databases (rs74315289, gnomAD 0.02%). This missense change has been observed in individual(s) with Bartter syndrome (PMID: 12574213, 16328537, 21865213, 26537508). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4387). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BSND protein function. Experimental studies have shown that this missense change affects BSND function (PMID: 11734858, 18776122). For these reasons, this variant has been classified as Pathogenic. -

Mar 03, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate the variant disrupts normal protein function (PMID: 18776122, 11734858); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21158220, 21269598, 16328537, 26537508, 21865213, 12574213, 16935888, 16572343, 31667618, 11734858, 34426522, 31589614, 31980526, 35314707, 35982159, 18776122) -

Bartter syndrome type 4

Pathogenic:1

Oct 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

BSND-related disorder

Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BSND c.139G>A variant is predicted to result in the amino acid substitution p.Gly47Arg. This variant has been reported to be causative for a mild form of Bartter syndrome (Janssen et al. 2009. PubMed ID: 18776122; Miyamura et al. 2003. PubMed ID: 12574213; Lee et al. 2012. PubMed ID: 21865213). This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Hearing loss, autosomal recessive

Pathogenic:1

May 01, 2024

Laboratory of Human Genetics, Universidade de São Paulo

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The BSND NM_057176.3:c.139G>A variant : For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases (PM3), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), Well-established functional studies show damaging effect on the gene or gene product (PS3), Extremely low frequency in gnomAD population databases (PM2). In this report it was found in homozygosis in one affected individual with Bartter syndrome, born from consanguineous parents. -

Bartter syndrome

Pathogenic:1

Feb 20, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

1.8

PhyloP100

3.6

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.49

Sift

Uncertain

0.027

Sift4G

Uncertain

0.041

Polyphen

1.0

Vest4

0.52

MutPred

0.81

Gain of MoRF binding (P = 0.073);

MVP

0.82

MPC

0.48

ClinPred

0.25

GERP RS

3.3

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.24

gMVP

0.82

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over