rs1555466999

Variant names:

• chr15-48244876-G-A
• rs1555466999
• NM_000338.3:c.1424G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000338.3(SLC12A1):​c.1424G>A​(p.Cys475Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A1 NM_000338.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60
• 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 15-48244876-G-A is Pathogenic according to our data. Variant chr15-48244876-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.1424G>A	p.Cys475Tyr	missense_variant	Exon 11 of 27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.1424G>A	p.Cys475Tyr	missense_variant	Exon 11 of 27		NP_001171761.1
SLC12A1	NM_001384136.1	c.1424G>A	p.Cys475Tyr	missense_variant	Exon 11 of 27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.1424G>A	p.Cys475Tyr	missense_variant	Exon 11 of 27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartter disease type 1 Pathogenic:2

May 01, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG: PS1, PM2, PP3, PP4 -

Feb 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1

Sep 08, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;.;D;.;D;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;D;.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;M;M;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.4	.;.;.;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.015	.;.;.;D;D;D;D
Sift4G	Uncertain	0.0050	.;.;.;D;D;D;D
Polyphen		1.0	.;.;D;.;D;D;.
Vest4		0.97, 0.97, 0.97
MutPred		0.86		Gain of phosphorylation at Y477 (P = 0.1149);.;Gain of phosphorylation at Y477 (P = 0.1149);.;Gain of phosphorylation at Y477 (P = 0.1149);Gain of phosphorylation at Y477 (P = 0.1149);Gain of phosphorylation at Y477 (P = 0.1149);
MVP		0.99
MPC		0.82
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555466999; hg19: chr15-48537073;