rs121908144

Positions:

• chr1-54999221-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_057176.3(BSND):​c.35T>C​(p.Ile12Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BSND NM_057176.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 7.00

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_057176.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 1-54999221-T-C is Pathogenic according to our data. Variant chr1-54999221-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-54999221-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSND	NM_057176.3	c.35T>C	p.Ile12Thr	missense_variant	1/4	ENST00000651561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSND	ENST00000651561.1	c.35T>C	p.Ile12Thr	missense_variant	1/4		NM_057176.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251442 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartter disease type 4A Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	This variant was previously reported in trans with another pathogenic variant in this gene (PMID: 19646679) and co-segregated with Sensorineural deafness with mild renal dysfunction in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 19646679). In addition, it was observed in multiple affected individuals with a consistent phenotype from unrelated families (PMID: 19646679). Functional assays showed that the variant had strong level of impact on gene/protein function (PMID: 19646679). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.941>=0.6, 3CNET: 0.815>=0.75). A missense variant is a common mechanism associated with Sensorineural deafness with mild renal dysfunction. It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 12 of the BSND protein (p.Ile12Thr). This variant is present in population databases (rs121908144, gnomAD 0.02%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 19646679, 21541222). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4388). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BSND protein function. Experimental studies have shown that this missense change affects BSND function (PMID: 19646679). For these reasons, this variant has been classified as Pathogenic. -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Sensorineural deafness with mild renal dysfunction Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2009

- -

Bartter syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 15, 2022

Variant summary: BSND c.35T>C (p.Ile12Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes. c.35T>C has been reported in the literature as homozygous genotypes in individuals affected with non-syndromic deafness and as a compound heterozygous genotype with another loss of function variant, c.10G>T (p.E4*), in individuals with features of Bartter Syndrome, Type 4a (example, Riazuddin_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating intact chloride channel function and impaired chaperone function of the protein in intracellular trafficking (Riazuddin_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.74		Loss of stability (P = 0.0326);
MVP		0.90
MPC		0.50
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.80
gMVP		0.91

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: rs121908144; hg19: chr1-55464894;