1-54999209-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_057176.3(BSND):c.23G>A(p.Arg8Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,614,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: BSND NM_057176.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.70

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity BSND_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_057176.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-54999208-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSND	NM_057176.3	c.23G>A	p.Arg8Gln	missense_variant	1/4	ENST00000651561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSND	ENST00000651561.1	c.23G>A	p.Arg8Gln	missense_variant	1/4		NM_057176.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251394 Hom.: 1 AF XY: 0.000110 AC XY: 15 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461834 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000521 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 14, 2023

Variant summary: BSND c.23G>A (p.Arg8Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251394 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in BSND causing Bartter Syndrome, Type 4a (9.5e-05 vs 0.0011), allowing no conclusion about variant significance. c.23G>A has been reported in the literature in the homozygous state in two individuals with bilateral sensorineural deafness, however both did not have any clear renal involvement/symptoms reported and one also had other clinical features not typically associated with Bartter Syndrome, Type 4a (Cabanilla_2018, Molina-Ramirez_2022). These reports do not provide unequivocal conclusions about association of the variant with Bartter Syndrome, Type 4a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, several variants affecting the same amino acid (ie. R8G, R8L, R8W) have been reported in association with Bartter syndrome with sensorineural deafness in the HGMD database, one of which (R8W) has also been classified as pathogenic by our laboratory, suggesting this residue is likely important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 29986705, 31706454, 33879512). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 06, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 8 of the BSND protein (p.Arg8Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with deafness (PMID: 29986705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg8 amino acid residue in BSND. Other variant(s) that disrupt this residue have been observed in individuals with BSND-related conditions (PMID: 11687798), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.98
MPC		0.48
ClinPred		0.75	D
GERP RS		4.4
Varity_R		0.76
gMVP		0.92

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: rs74315288; hg19: chr1-55464882; COSMIC: COSV100987657;