rs11643718

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.2711G>A(p.Arg904Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,514 control chromosomes in the GnomAD database, including 9,371 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R904W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.085 ( 737 hom., cov: 33)

Exomes 𝑓: 0.11 ( 8634 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.30

Publications

84 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 -19 ACMG points.

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=0.0014933348).

BP6

Variant 16-56899607-G-A is Benign according to our data. Variant chr16-56899607-G-A is described in ClinVar as Benign. ClinVar VariationId is 255888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2711G>A	p.Arg904Gln	missense_variant	Exon 23 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2738G>A	p.Arg913Gln	missense_variant	Exon 23 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2735G>A	p.Arg912Gln	missense_variant	Exon 23 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2708G>A	p.Arg903Gln	missense_variant	Exon 23 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.2711G>A	p.Arg904Gln	missense_variant	Exon 23 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.2738G>A	p.Arg913Gln	missense_variant	Exon 23 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.2735G>A	p.Arg912Gln	missense_variant	Exon 23 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.2708G>A	p.Arg903Gln	missense_variant	Exon 23 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0854

AC:

12997

AN:

152170

Hom.:

736

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.0859

Gnomad EAS

AF:

0.0741

Gnomad SAS

AF:

0.0909

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.109

AC:

27318

AN:

251438

AF XY:

0.108

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.0870

Gnomad EAS exome

AF:

0.0756

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.106

AC:

155243

AN:

1460226

Hom.:

8634

Cov.:

AF XY:

0.106

AC XY:

77237

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.0185

AC:

618

AN:

33446

American (AMR)

AF:

0.166

AC:

7413

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0886

AC:

2314

AN:

26126

East Asian (EAS)

AF:

0.0679

AC:

2693

AN:

39690

South Asian (SAS)

AF:

0.0933

AC:

8049

AN:

86228

European-Finnish (FIN)

AF:

0.126

AC:

6719

AN:

53406

Middle Eastern (MID)

AF:

0.132

AC:

763

AN:

5768

European-Non Finnish (NFE)

AF:

0.109

AC:

120606

AN:

1110492

Other (OTH)

AF:

0.101

AC:

6068

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

6774

13548

20321

27095

33869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4410

8820

13230

17640

22050

<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:

0.0853

AC:

12996

AN:

152288

Hom.:

737

Cov.:

AF XY:

0.0875

AC XY:

6511

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0213

AC:

886

AN:

41580

American (AMR)

AF:

0.129

AC:

1972

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0859

AC:

298

AN:

3470

East Asian (EAS)

AF:

0.0745

AC:

386

AN:

5184

South Asian (SAS)

AF:

0.0909

AC:

439

AN:

4828

European-Finnish (FIN)

AF:

0.127

AC:

1345

AN:

10588

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7398

AN:

68022

Other (OTH)

AF:

0.107

AC:

226

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

617

1235

1852

2470

3087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.103

Hom.:

3412

Bravo

AF:

0.0850

TwinsUK

AF:

0.112

AC:

417

ALSPAC

AF:

0.105

AC:

406

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.104

AC:

894

ExAC

AF:

0.103

AC:

12563

Asia WGS

AF:

0.0830

AC:

289

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.118

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25401745, 24776766, 15480096, 9734597, 10988270, 28008009, 28744814, 32292023, 31398183) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.073

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.17

.;.;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.73

T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

.;.;N;.

PhyloP100

1.3

PrimateAI

Benign

0.20

PROVEAN

Benign

0.51

N;N;N;N

REVEL

Benign

0.015

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.85

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.076

MPC

0.10

ClinPred

0.0022

GERP RS

1.7

Varity_R

0.051

gMVP

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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