rs121908144
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_057176.3(BSND):āc.35T>Cā(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 (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.000012 ( 0 hom. )
Consequence
BSND
NM_057176.3 missense
NM_057176.3 missense
Scores
12
4
3
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251442Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135902
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727242
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bartter disease type 4A Pathogenic:1Uncertain: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.0326);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at