rs752101663

Positions:

chr16-56887937-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001126108.2(SLC12A3):c.2191G>A(p.Gly731Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.76

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 16-56887937-G-A is Pathogenic according to our data. Variant chr16-56887937-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 linkuse as main transcript	c.2191G>A	p.Gly731Arg	missense_variant	18/26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 linkuse as main transcript	c.2191G>A	p.Gly731Arg	missense_variant	18/26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2188G>A	p.Gly730Arg	missense_variant	18/26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2188G>A	p.Gly730Arg	missense_variant	18/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.2191G>A	p.Gly731Arg	missense_variant	18/26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.2191G>A	p.Gly731Arg	missense_variant	18/26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.2188G>A	p.Gly730Arg	missense_variant	18/26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.2188G>A	p.Gly730Arg	missense_variant	18/26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

151414

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251158

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460702

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151414

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73922

show subpopulations

Gnomad4 AFR

AF:

0.0000729

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Apr 13, 2020	The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the 731 position to arginine (p.Gly731Arg). This variant localizes to coding exon 18 of the SLC12A3 gene (26 exons total; NM_000339.3). This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (PROVEAN and SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00002837, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple individuals with Gitelman syndrome either in the homozygous state or with another SLC12A3 variant (PMIDs: 17699451, 21415153, 30596175, 25422309). -
Pathogenic, criteria provided, single submitter	clinical testing	European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	Apr 27, 2022	ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 29, 2024	- -

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). This variant is present in population databases (rs752101663, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 12112667, 21415153, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 562347). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;.;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.5

.;M;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.5

D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.98

D;P;P;.

Vest4

0.98

MutPred

0.92

.;Gain of MoRF binding (P = 0.0195);Gain of MoRF binding (P = 0.0195);.;

MVP

0.98

MPC

0.29

ClinPred

0.99

GERP RS

4.7

Varity_R

0.87

gMVP

0.94

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