1-54999142-C-CCCCCTCTCCCGGGGGTGTGCAGGCCAGGGACTGGCCAGGCAG

Variant names:

• chr1-54999142-C-CCCCCTCTCCCGGGGGTGTGCAGGCCAGGGACTGGCCAGGCAG
• NM_057176.3:c.-42_-1dupCCTCTCCCGGGGGTGTGCAGGCCAGGGACTGGCCAGGCAGCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_057176.3(BSND):​c.-42_-1dupCCTCTCCCGGGGGTGTGCAGGCCAGGGACTGGCCAGGCAGCC variant causes a start lost, conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BSND NM_057176.3 start_lost, conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.494

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 Pathogenic. Variant got 12 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BSND	NM_057176.3	c.-42_-1dupCCTCTCCCGGGGGTGTGCAGGCCAGGGACTGGCCAGGCAGCC		start_lost, conservative_inframe_insertion	Exon 1 of 4	ENST00000651561.1	NP_476517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BSND	ENST00000651561.1	c.-42_-1dupCCTCTCCCGGGGGTGTGCAGGCCAGGGACTGGCCAGGCAGCC		start_lost, conservative_inframe_insertion	Exon 1 of 4		NM_057176.3	ENSP00000498282.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BSND c.-42_-1dup is located in the untranslated mRNA region upstream of the initiation codon. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 151830 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-42_-1dup in individuals affected with Bartter Syndrome, Type 4a and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-55464815;