15-48259183-CTT-CTTTT

Variant names:

• chr15-48259183-C-CTT
• rs112495679
• NM_000338.3:c.2043-10_2043-9dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000338.3(SLC12A1):​c.2043-10_2043-9dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,377,166 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: SLC12A1 NM_000338.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

Genes affected

SLC12A1 (HGNC:10910): (solute carrier family 12 member 1) This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

SLC12A1 Gene-Disease associations (from GenCC):

• Bartter disease type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• antenatal Bartter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.2043-10_2043-9dupTT		splice_region_variant, intron_variant	Intron 16 of 26	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.2043-10_2043-9dupTT		splice_region_variant, intron_variant	Intron 16 of 26		NP_001171761.1
SLC12A1	NM_001384136.1	c.2043-10_2043-9dupTT		splice_region_variant, intron_variant	Intron 16 of 26		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.2043-17_2043-16insTT		intron_variant	Intron 16 of 26	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000581 AC: 8 AN: 1377166 Hom.: 0 Cov.: 24 AF XY: 0.00000580 AC XY: 4 AN XY: 690042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000315 AC: 1 AN: 31778

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25562

East Asian (EAS) AF: 0.00 AC: 0 AN: 39248

South Asian (SAS) AF: 0.00 AC: 0 AN: 84376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 0.00000676 AC: 7 AN: 1035448

Other (OTH) AF: 0.00 AC: 0 AN: 57376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

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

Other links and lift over

dbSNP: rs112495679; hg19: chr15-48551380;