# NM_057176.3(BSND):c.22C>T (p.Arg8Trp)

https://sugi.bio/variant/bsnd-p-arg8trp

## Summary

**BSND p.Arg8Trp (c.22C>T)** is classified **Pathogenic/Likely pathogenic** in BSND (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-31). AlphaMissense: likely pathogenic (0.7596); Very rare (popmax 0.00892%, eas); Associated with Bartter syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs74315285 · 5 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00892%, eas)

## For patients & families {#patients}

This is a change in the BSND gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to Bartter syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BSND is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Bartter syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005893/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BSND](https://sugi.bio/atlas/gene/BSND/) |
| Protein change (HGVS p.) | p.Arg8Trp |
| Coding change (HGVS c.) | c.22C>T |
| MANE Select transcript | [NM_057176](https://www.ncbi.nlm.nih.gov/nuccore/NM_057176) |
| dbSNP | [rs74315285](https://www.ncbi.nlm.nih.gov/snp/rs74315285/) |
| Variant type | single nucleotide variant |
| Location | chr1:54999208-54999208 (GRCh38) |
| ClinVar | [VCV4381](https://www.ncbi.nlm.nih.gov/clinvar/variation/4381/) |

**All HGVS expressions:** `LRG_1282:g.5276C>T`, `LRG_1282t1:c.22C>T`, `NC_000001.10:g.55464881C>T`, `NC_000001.11:g.54999208C>T`, `NG_008965.2:g.5276C>T`, `NM_057176.3:c.22C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7596) — concordant with the pathogenic call
- REVEL 0.916 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.671 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 5.906, GERP 1.39, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in BSND (of 1,896 modeled).
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (54,999,187–55,008,625), spanning 9,438 bp. Chi-square p 0.065. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00892%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,866 in the highest group · 40/1,614,140 alleles overall — very rare (popmax 0.00892%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00892% | 11,216 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| European (non-Finnish) | 0.00263% | 38,065 |
| South Asian | 0.0022% | 45,543 |
| African / African-American | 0.00133% | 75,046 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BSND** population constraint: LOEUF 1.03, pLI 0.00065519, missense-Z 1.0448; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Bartter disease type 4A** — Definitive (AR)

## Protein context {#protein}

Residue **8** lies in a UniProt-annotated variant site (in barts4a); a UniProt-annotated variant site (in barts4a; fails to activate clcnka and clcnkb channels); a UniProt-annotated variant site (in barts4a; fails to activate clcnka and clcnkb channels; loss of channel conductance); the 'regulates channel membrane trafficking and ion conductance' region.

AlphaFold model confidence (whole protein): pLDDT 53.80, 0% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of BSND (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BSND's established molecular role includes chloride channel regulator activity. p.Arg8Trp falls in the regulates channel membrane trafficking and ion conductance region.


### Pathways affected {#pathways}

BSND participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** chloride channel regulator activity.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-31.

**Submitter consensus:** conflicting (3 Likely pathogenic, 2 Pathogenic).

**Submission history:** 5 submissions (2001–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-31 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-13 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2001-11-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-29 |

## Associated conditions {#conditions}

[Bartter syndrome](https://sugi.bio/atlas/disease/bartter-syndrome/), [Bartter disease type 4A](https://sugi.bio/atlas/disease/bartter-disease-type-4a/).

**Reported phenotype names (ClinVar):** Bartter syndrome, Bartter disease type 4A, not provided, none provided, BARTTER SYNDROME, TYPE 4A, NEONATAL, WITH SENSORINEURAL DEAFNESS, BARTTER SYNDROME, NEONATAL, WITH SENSORINEURAL DEAFNESS.

## Same-residue context {#hotspot}

Residue **8** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BSND p.Arg8Gly](/variant/bsnd-p-arg8gly), [BSND p.Arg8Leu](/variant/bsnd-p-arg8leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BSND variant pages (same residue, condition, or type): [BSND p.Arg8Gln](/variant/bsnd-p-arg8gln), [BSND p.Arg8Leu](/variant/bsnd-p-arg8leu), [BSND p.Arg8Gly](/variant/bsnd-p-arg8gly), [BSND p.Arg8=](/variant/bsnd-p-arg8), [BSND c.178-2A>C](/variant/bsnd-c-178-minus-2a-c), [BSND c.272+1G>T](/variant/bsnd-c-272-plus-1g-t), [BSND p.Gln95Ter](/variant/bsnd-p-gln95ter), [BSND p.Glu148Ter](/variant/bsnd-p-glu148ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4381). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*