rs12708965

Positions:

chr16-56902407-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.2755C>T(p.Arg919Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,612,492 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 144 hom., cov: 31)

Exomes 𝑓: 0.018 ( 479 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.63

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 links:

SLC12A3 (HGNC:):

SLC12A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004836887).

BP6

Variant 16-56902407-C-T is Benign according to our data. Variant chr16-56902407-C-T is described in ClinVar as [Benign]. Clinvar id is 319917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56902407-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 linkuse as main transcript	c.2755C>T	p.Arg919Cys	missense_variant	24/26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 linkuse as main transcript	c.2782C>T	p.Arg928Cys	missense_variant	24/26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2779C>T	p.Arg927Cys	missense_variant	24/26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2752C>T	p.Arg918Cys	missense_variant	24/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.2755C>T	p.Arg919Cys	missense_variant	24/26	1	NM_001126108.2	ENSP00000456149.2		P55017-1

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

5305

AN:

151820

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0703

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0384

Gnomad ASJ

AF:

0.0588

Gnomad EAS

AF:

0.0248

Gnomad SAS

AF:

0.0493

Gnomad FIN

AF:

0.0320

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0393

GnomAD3 exomes

AF:

0.0311

AC:

7811

AN:

251468

Hom.:

207

AF XY:

0.0303

AC XY:

4115

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0739

Gnomad AMR exome

AF:

0.0443

Gnomad ASJ exome

AF:

0.0670

Gnomad EAS exome

AF:

0.0266

Gnomad SAS exome

AF:

0.0501

Gnomad FIN exome

AF:

0.0320

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.0324

GnomAD4 exome

AF:

0.0183

AC:

26757

AN:

1460554

Hom.:

479

Cov.:

AF XY:

0.0191

AC XY:

13876

AN XY:

726546

show subpopulations

Gnomad4 AFR exome

AF:

0.0728

Gnomad4 AMR exome

AF:

0.0448

Gnomad4 ASJ exome

AF:

0.0689

Gnomad4 EAS exome

AF:

0.0227

Gnomad4 SAS exome

AF:

0.0477

Gnomad4 FIN exome

AF:

0.0311

Gnomad4 NFE exome

AF:

0.0108

Gnomad4 OTH exome

AF:

0.0263

GnomAD4 genome

AF:

0.0349

AC:

5308

AN:

151938

Hom.:

144

Cov.:

AF XY:

0.0351

AC XY:

2603

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.0701

Gnomad4 AMR

AF:

0.0385

Gnomad4 ASJ

AF:

0.0588

Gnomad4 EAS

AF:

0.0248

Gnomad4 SAS

AF:

0.0491

Gnomad4 FIN

AF:

0.0320

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.0389

Alfa

AF:

0.0203

Hom.:

Bravo

AF:

0.0375

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.0680

AC:

299

ESP6500EA

AF:

0.0173

AC:

149

ExAC

AF:

0.0306

AC:

3710

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0124

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:6

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg928Cys variant in SLC12A3 has been identified in an individual with Gitelman syndrome (PMID: 9734597). This variant is classified as benign for autosomal recessive Gitelman syndrome because it has been identified in >70% of African chromosomes and 107 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2020	This variant is associated with the following publications: (PMID: 25273610, 17885550, 20981092, 9734597, 27884173, 27535533, 19489442, 31660880, 31398183) -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;.;D;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.95

D;D;D;D

MetaRNN

Benign

0.0048

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

.;.;M;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.6

D;D;D;D

REVEL

Uncertain

0.38

Sift

Benign

0.035

D;D;D;D

Sift4G

Uncertain

0.052

T;T;T;T

Polyphen

0.53

P;D;D;.

Vest4

0.31

MPC

0.50

ClinPred

0.037

GERP RS

4.0

Varity_R

0.53

gMVP

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over