chr1-54999187-A-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_057176.3(BSND):c.1A>T(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,720 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: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BSND
NM_057176.3 start_lost
NM_057176.3 start_lost
Scores
10
5
1
Clinical Significance
Conservation
PhyloP100: 8.12
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_057176.3 (BSND) was described as [Likely_pathogenic] in ClinVar as 4384
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-54999187-A-T is Pathogenic according to our data. Variant chr1-54999187-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 4380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-54999187-A-T is described in Lovd as [Pathogenic]. Variant chr1-54999187-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BSND | NM_057176.3 | c.1A>T | p.Met1? | start_lost | 1/4 | ENST00000651561.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BSND | ENST00000651561.1 | c.1A>T | p.Met1? | start_lost | 1/4 | NM_057176.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251270Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461720Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727170
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2022 | This sequence change affects the initiator methionine of the BSND mRNA. The next in-frame methionine is located at codon 26. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BSND protein in which other variant(s) (p.Ile12Thr) have been determined to be pathogenic (PMID: 19646679, 21541222). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 4380). This variant is also known as A1T. Disruption of the initiator codon has been observed in individuals with Bartter syndrome (PMID: 11687798, 16773427). This variant is present in population databases (rs74315284, gnomAD 0.0009%). - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Bartter disease type 4A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jan 24, 2022 | ACMG categories: PVS1,PM2,PP5 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Loss of methylation at K5 (P = 0.0878);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at