# NM_057176.3(BSND):c.452del (p.Pro151fs)

https://sugi.bio/variant/bsnd-p-pro151fs

## Summary

**BSND p.Pro151fs (c.452del)** is classified **Conflicting classifications of pathogenicity** in BSND (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-03). Ultra-rare (popmax 0.034%, sas); Associated with Bartter disease type 4A.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs765135576 · 6 submitters · 1 linked condition · ultra-rare (popmax 0.034%, sas)

## For patients & families {#patients}

This is a change in the BSND gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Bartter disease type 4A.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015348/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.Pro151fs |
| Coding change (HGVS c.) | c.452del |
| MANE Select transcript | [NM_057176](https://www.ncbi.nlm.nih.gov/nuccore/NM_057176) |
| dbSNP | [rs765135576](https://www.ncbi.nlm.nih.gov/snp/rs765135576/) |
| Variant type | Deletion |
| Location | chr1:55007174-55007174 (GRCh38) |
| ClinVar | [VCV590851](https://www.ncbi.nlm.nih.gov/clinvar/variation/590851/) |

**All HGVS expressions:** `LRG_1282:g.13244del`, `LRG_1282t1:c.452del`, `NC_000001.10:g.55472849del`, `NC_000001.11:g.55007176del`, `NG_008965.2:g.13244del`, `NM_057176.3:c.450del`, `NM_057176.3:c.452del`, `NM_057176.3:c.452delC`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.034, GERP 1.25, phastCons 0.865 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.03, pLI 0.00065519. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 4**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 19.52**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.034%** (sas) · FAF95 0.0246% · FAF99 0.0214% · 31/91,086 in the highest group · 37/1,614,086 alleles overall — ultra-rare (popmax 0.034%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.034% | 2,938 |
| African / African-American | 0.00133% | 74,924 |
| European (non-Finnish) | 0.000424% | 236,010 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **151** lies in a UniProt-annotated variant site (in barts4a); a UniProt-annotated variant site (in barts4a; loss of clcnka and clcnkb channel conductance); a UniProt-annotated variant site (in barts4a; abolishes the preferential sorting at the basolateral membrane domain; no effect on ion conductance).

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.Pro151fs falls in a UniProt-annotated variant site (in barts4a; abolishes the preferential sorting at the basolateral membrane domain; no effect on ion conductance).


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-03.

**Submitter consensus:** conflicting (3 Pathogenic, 2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 6 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-13 |
| Felix Claverie-Martin Laboratory, Hospital Universitario Nuestra Senora de Candelaria | Pathogenic | no assertion criteria provided | clinical testing |  |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-20 |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic | Likely pathogenic | criteria provided, single submitter | research | 2025-10-03 |
| Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-20 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related BSND variant pages (same residue, condition, or type): [BSND c.157_177+20del](/variant/bsnd-c-157-177-plus-20del), [BSND c.273-887_*576del](/variant/bsnd-c-273-minus-887-star-576del), [BSND c.272+1G>T](/variant/bsnd-c-272-plus-1g-t), [BSND p.Arg8Trp](/variant/bsnd-p-arg8trp), [BSND p.Glu4Ter](/variant/bsnd-p-glu4ter), [BSND p.Glu88Ter](/variant/bsnd-p-glu88ter), [BSND p.Gly10Ser](/variant/bsnd-p-gly10ser), [BSND p.Gly47Arg](/variant/bsnd-p-gly47arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 590851). 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.*