rs36049418

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 15/20 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

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:

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=0.009306401).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC12A3	NM_001126108.2 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/26		NP_000330.3
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2179G>A	p.Ala727Thr	missense_variant	18/26		NP_001119579.2
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2179G>A	p.Ala727Thr	missense_variant	18/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/26	1	NM_001126108.2	ENSP00000456149	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/26	1		ENSP00000402152	A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.2179G>A	p.Ala727Thr	missense_variant	18/26	1		ENSP00000457552	P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.2179G>A	p.Ala727Thr	missense_variant	18/26	5		ENSP00000262502	A1

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

GnomAD3 exomes

AF:

0.0121

AC:

3042

AN:

251000

Hom.:

AF XY:

0.0129

AC XY:

1749

AN XY:

135796

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 SAS exome

AF:

0.00934

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

Gnomad4 AFR exome

AF:

0.00329

Gnomad4 AMR exome

AF:

0.00575

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0103

Gnomad4 FIN exome

AF:

0.00936

Gnomad4 NFE exome

AF:

0.0227

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0128

AC:

1932

AN:

151094

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

901

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0105

Gnomad4 FIN

AF:

0.00752

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.0120

Alfa

AF:

0.0170

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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 25, 2019	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	This variant is associated with the following publications: (PMID: 27535533, 27884173, 8528245, 20981092, 24633158) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SLC12A3: BP4, BS1, BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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% -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

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;.

MutationTaster

Benign

1.0

N;N;N;N

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

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

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