rs36049418

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001126108.2(SLC12A3):c.2182G>A(p.Ala728Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,609,578 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 30)

Exomes 𝑓: 0.019 ( 353 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.13

Publications

19 publications found

Variant links:

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SLC12A3 Gene-Disease associations (from GenCC):

Gitelman syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

SLC12A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001126108.2

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.009306401).

BP6

Variant 16-56887928-G-A is Benign according to our data. Variant chr16-56887928-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1932/151094) while in subpopulation NFE AF = 0.0196 (1330/67804). AF 95% confidence interval is 0.0187. There are 19 homozygotes in GnomAd4. There are 901 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC12A3	NM_001126108.2 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 26		NP_000330.3
SLC12A3	NM_001126107.2 link	c.2179G>A	p.Ala727Thr	missense_variant	Exon 18 of 26		NP_001119579.2
SLC12A3	NM_001410896.1 link	c.2179G>A	p.Ala727Thr	missense_variant	Exon 18 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC12A3	ENST00000563236.6 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5 link	c.2179G>A	p.Ala727Thr	missense_variant	Exon 18 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5 link	c.2179G>A	p.Ala727Thr	missense_variant	Exon 18 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1933

AN:

150986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.0703

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0107

Gnomad FIN

AF:

0.00752

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0121

GnomAD2 exomes

AF:

0.0121

AC:

3042

AN:

251000

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00989

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0194

AC:

28262

AN:

1458484

Hom.:

353

Cov.:

AF XY:

0.0189

AC XY:

13750

AN XY:

725638

show subpopulations

African (AFR)

AF:

0.00329

AC:

110

AN:

33400

American (AMR)

AF:

0.00575

AC:

257

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

289

AN:

26050

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39622

South Asian (SAS)

AF:

0.0103

AC:

890

AN:

86230

European-Finnish (FIN)

AF:

0.00936

AC:

495

AN:

52890

Middle Eastern (MID)

AF:

0.00750

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0227

AC:

25205

AN:

1109682

Other (OTH)

AF:

0.0161

AC:

970

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

1307

2613

3920

5226

6533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

988

1976

2964

3952

4940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0128

AC:

1932

AN:

151094

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

901

AN XY:

73792

show subpopulations

African (AFR)

AF:

0.00409

AC:

168

AN:

41112

American (AMR)

AF:

0.0115

AC:

174

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.0105

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00752

AC:

AN:

10372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0196

AC:

1330

AN:

67804

Other (OTH)

AF:

0.0120

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0162

Hom.:

Bravo

AF:

0.0129

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0197

AC:

169

ExAC

AF:

0.0121

AC:

1465

EpiCase

AF:

0.0196

EpiControl

AF:

0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Oct 25, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Ala728Thr variant in SLC12A3 has been identified in an individual from the Philippines with Gitelman syndrome (PMID: 8528245), but has also been identified in >1% of European (non-Finnish) chromosomes and 27 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Gitelman syndrome. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27535533, 27884173, 8528245, 20981092, 24633158) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC12A3: BP4, BS1, BS2 -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 188/12996=1.44% -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

2.7

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.34

.;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.76

T;T;T;T

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.38

.;N;N;.

PhyloP100

-1.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.91

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.23

T;T;T;T

Sift4G

Benign

0.71

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.053

MPC

0.085

ClinPred

0.00031

GERP RS

-0.68

Varity_R

0.064

gMVP

0.68

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over