rs5802

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001126108.2(SLC12A3):c.1884G>A(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0933 in 1,555,250 control chromosomes in the GnomAD database, including 7,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 616 hom., cov: 32)

Exomes 𝑓: 0.095 ( 6552 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -6.14

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-56885323-G-A is Benign according to our data. Variant chr16-56885323-G-A is described in ClinVar as Benign. ClinVar VariationId is 255883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC12A3	NM_001126108.2 link	c.1884G>A	p.Ser628Ser	synonymous_variant	Exon 15 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 link	c.1884G>A	p.Ser628Ser	synonymous_variant	Exon 15 of 26		NP_000330.3
SLC12A3	NM_001126107.2 link	c.1881G>A	p.Ser627Ser	synonymous_variant	Exon 15 of 26		NP_001119579.2
SLC12A3	NM_001410896.1 link	c.1881G>A	p.Ser627Ser	synonymous_variant	Exon 15 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC12A3	ENST00000563236.6 link	c.1884G>A	p.Ser628Ser	synonymous_variant	Exon 15 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6 link	c.1884G>A	p.Ser628Ser	synonymous_variant	Exon 15 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5 link	c.1881G>A	p.Ser627Ser	synonymous_variant	Exon 15 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5 link	c.1881G>A	p.Ser627Ser	synonymous_variant	Exon 15 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes

AF:

0.0808

AC:

12287

AN:

152112

Hom.:

614

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0768

Gnomad ASJ

AF:

0.0836

Gnomad EAS

AF:

0.0484

Gnomad SAS

AF:

0.0758

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0995

Gnomad OTH

AF:

0.0986

GnomAD2 exomes

AF:

0.0854

AC:

13926

AN:

163130

AF XY:

0.0872

show subpopulations

Gnomad AFR exome

AF:

0.0414

Gnomad AMR exome

AF:

0.0565

Gnomad ASJ exome

AF:

0.0875

Gnomad EAS exome

AF:

0.0510

Gnomad FIN exome

AF:

0.128

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.0947

AC:

132878

AN:

1403020

Hom.:

6552

Cov.:

AF XY:

0.0948

AC XY:

65660

AN XY:

692444

show subpopulations

African (AFR)

AF:

0.0431

AC:

1373

AN:

31846

American (AMR)

AF:

0.0577

AC:

2093

AN:

36248

Ashkenazi Jewish (ASJ)

AF:

0.0890

AC:

2243

AN:

25192

East Asian (EAS)

AF:

0.0331

AC:

1200

AN:

36204

South Asian (SAS)

AF:

0.0771

AC:

6123

AN:

79400

European-Finnish (FIN)

AF:

0.124

AC:

6164

AN:

49512

Middle Eastern (MID)

AF:

0.130

AC:

741

AN:

5702

European-Non Finnish (NFE)

AF:

0.0995

AC:

107558

AN:

1080760

Other (OTH)

AF:

0.0926

AC:

5383

AN:

58156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

6165

12330

18496

24661

30826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3952

7904

11856

15808

19760

<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:

0.0808

AC:

12298

AN:

152230

Hom.:

616

Cov.:

AF XY:

0.0817

AC XY:

6081

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0445

AC:

1849

AN:

41540

American (AMR)

AF:

0.0767

AC:

1173

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0836

AC:

290

AN:

3468

East Asian (EAS)

AF:

0.0484

AC:

251

AN:

5190

South Asian (SAS)

AF:

0.0759

AC:

366

AN:

4824

European-Finnish (FIN)

AF:

0.126

AC:

1340

AN:

10596

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0996

AC:

6772

AN:

68004

Other (OTH)

AF:

0.0975

AC:

206

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

600

1199

1799

2398

2998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0901

Hom.:

758

Bravo

AF:

0.0752

Asia WGS

AF:

0.0670

AC:

232

AN:

3478

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

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 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. -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.32

(source)

DANN

Benign

0.38

PhyloP100

-6.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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