rs144505461

Positions:

• chr1-55005033-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_057176.3(BSND):​c.189C>T​(p.Val63Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,204 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (20 hom.)
• Consequence: BSND NM_057176.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.68

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=-0.61).
• BP6: Variant 1-55005033-C-T is Benign according to our data. Variant chr1-55005033-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55005033-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00147 (224/152350) while in subpopulation SAS AF= 0.00705 (34/4822). AF 95% confidence interval is 0.00519. There are 2 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BSND	NM_057176.3	c.189C>T	p.Val63Val	synonymous_variant	2/4	ENST00000651561.1	NP_476517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BSND	ENST00000651561.1	c.189C>T	p.Val63Val	synonymous_variant	2/4		NM_057176.3	ENSP00000498282.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152232 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00252 AC: 633 AN: 251416 Hom.: 3 AF XY: 0.00288 AC XY: 392 AN XY: 135882

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00794

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00205 AC: 2995 AN: 1461854 Hom.: 20 Cov.: 31 AF XY: 0.00222 AC XY: 1611 AN XY: 727232

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00750

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152350 Hom.: 2 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74510

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00175

Asia WGS AF: 0.00260 AC: 11 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	BSND: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2015	p.Val63Val in exon 02 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 0.7% of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs144505461). -

Bartter disease type 4A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bartter syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.15
DANN	Benign	0.67

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: rs144505461; hg19: chr1-55470706;