rs12594698

Variant names:

• chr15-48282759-C-T
• rs12594698
• NM_000338.3:c.2486-2347C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000338.3(SLC12A1):​c.2486-2347C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 151,970 control chromosomes in the GnomAD database, including 6,727 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6727 hom., cov: 32)
• Consequence: SLC12A1 NM_000338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• Publications: 2 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):

• antenatal Bartter syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Bartter disease type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000309916 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	NM_000338.3	MANE Select	c.2486-2347C>T		intron	N/A	NP_000329.2	Q13621-1
	SLC12A1	NM_001184832.2		c.2486-2347C>T		intron	N/A	NP_001171761.1	Q13621-3
	SLC12A1	NM_001384136.1		c.2486-2347C>T		intron	N/A	NP_001371065.1	A0A8I5KSK6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	ENST00000380993.8	TSL:5 MANE Select	c.2486-2347C>T		intron	N/A	ENSP00000370381.3	Q13621-1
	SLC12A1	ENST00000558252.5	TSL:1	n.6609-2347C>T		intron	N/A
	SLC12A1	ENST00000560692.5	TSL:1	n.6625-2347C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41712 AN: 151852 Hom.: 6699 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.270

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.275 AC: 41794 AN: 151970 Hom.: 6727 Cov.: 32 AF XY: 0.274 AC XY: 20353 AN XY: 74280

African (AFR) AF: 0.434 AC: 17985 AN: 41400

American (AMR) AF: 0.270 AC: 4122 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 759 AN: 3466

East Asian (EAS) AF: 0.412 AC: 2126 AN: 5160

South Asian (SAS) AF: 0.237 AC: 1139 AN: 4812

European-Finnish (FIN) AF: 0.208 AC: 2193 AN: 10566

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12776 AN: 67976

Other (OTH) AF: 0.276 AC: 585 AN: 2116

Alfa AF: 0.214 Hom.: 1840

Bravo AF: 0.286

Asia WGS AF: 0.370 AC: 1287 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.0
DANN	Benign	0.63
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12594698; hg19: chr15-48574956;