rs33938617

Positions:

• chr1-55008589-G-A
• chr1-55008589-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_057176.3(BSND):​c.924G>A​(p.Pro308=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,613,940 control chromosomes in the GnomAD database, including 31,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2695 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28612 hom.)
• Consequence: BSND NM_057176.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.67

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-55008589-G-A is Benign according to our data. Variant chr1-55008589-G-A is described in ClinVar as [Benign]. Clinvar id is 46553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BSND	NM_057176.3	c.924G>A	p.Pro308=	synonymous_variant	4/4	ENST00000651561.1	NP_476517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BSND	ENST00000651561.1	c.924G>A	p.Pro308=	synonymous_variant	4/4		NM_057176.3	ENSP00000498282	P1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27167 AN: 151960 Hom.: 2688 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0824

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.151 AC: 37999 AN: 250858 Hom.: 3609 AF XY: 0.152 AC XY: 20615 AN XY: 135624

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0822

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0794

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.191 AC: 279283 AN: 1461862 Hom.: 28612 Cov.: 34 AF XY: 0.187 AC XY: 136184 AN XY: 727238

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.0872

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0849

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.179 AC: 27190 AN: 152078 Hom.: 2695 Cov.: 32 AF XY: 0.172 AC XY: 12750 AN XY: 74340

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.0821

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.155

Alfa AF: 0.177 Hom.: 1344

Bravo AF: 0.176

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.201

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro308Pro in Exon 04 of BSND: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 20.5% (1438/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs33938617). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Bartter disease type 4A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Bartter syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.022
DANN	Benign	0.33

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

LitVar

Other links and lift over

dbSNP: rs33938617; hg19: chr1-55474262; COSMIC: COSV64870714;