rs199832638

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_057176.3(BSND):​c.806G>A​(p.Arg269Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

BSND
NM_057176.3 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -4.16
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.032109022).
BP6
Variant 1-55008471-G-A is Benign according to our data. Variant chr1-55008471-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504521.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BSNDNM_057176.3 linkuse as main transcriptc.806G>A p.Arg269Gln missense_variant 4/4 ENST00000651561.1 NP_476517.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BSNDENST00000651561.1 linkuse as main transcriptc.806G>A p.Arg269Gln missense_variant 4/4 NM_057176.3 ENSP00000498282 P1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000120
AC:
30
AN:
251042
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135744
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.000817
GnomAD4 exome
AF:
0.000141
AC:
206
AN:
1461832
Hom.:
0
Cov.:
31
AF XY:
0.000131
AC XY:
95
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000147
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000181
Hom.:
0
Bravo
AF:
0.000121
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000164
EpiControl
AF:
0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 23, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 269 of the BSND protein (p.Arg269Gln). This variant is present in population databases (rs199832638, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BSND-related conditions. ClinVar contains an entry for this variant (Variation ID: 504521). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 05, 2024In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 19, 2017p.Arg269Gln in exon 4 of BSND: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, >10 mammals have a glutamine (Gln) at this position. In addition, computatio nal prediction tools do not suggest a high likelihood of impact to the protein. It has been identified in 10/66322 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199832638). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
0.0010
DANN
Benign
0.70
DEOGEN2
Benign
0.25
T
Eigen
Benign
-2.2
Eigen_PC
Benign
-2.4
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.34
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.032
T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.18
T
PROVEAN
Benign
-0.18
N
REVEL
Benign
0.23
Sift
Benign
0.39
T
Sift4G
Benign
0.51
T
Polyphen
0.0
B
Vest4
0.033
MVP
0.35
MPC
0.090
ClinPred
0.0087
T
GERP RS
-9.1
Varity_R
0.018
gMVP
0.042

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199832638; hg19: chr1-55474144; API