NM_001126108.2:c.2470T>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001126108.2(SLC12A3):c.2470T>A(p.Ser824Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000838 in 1,614,216 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S824S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 1 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 2.18

Publications

4 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: Likely_benign. The variant received -1 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=0.07682854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2470T>A	p.Ser824Thr	missense_variant	Exon 21 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2497T>A	p.Ser833Thr	missense_variant	Exon 21 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2494T>A	p.Ser832Thr	missense_variant	Exon 21 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2467T>A	p.Ser823Thr	missense_variant	Exon 21 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.2470T>A	p.Ser824Thr	missense_variant	Exon 21 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.2497T>A	p.Ser833Thr	missense_variant	Exon 21 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.2494T>A	p.Ser832Thr	missense_variant	Exon 21 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.2467T>A	p.Ser823Thr	missense_variant	Exon 21 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000398

AC:

100

AN:

251062

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000696

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000868

AC:

1269

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000818

AC XY:

595

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.000559

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00108

AC:

1196

AN:

1111990

Other (OTH)

AF:

0.000613

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.000551

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41590

American (AMR)

AF:

0.00131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000686

Hom.:

Bravo

AF:

0.000597

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Uncertain:4

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:3

Aug 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 833 of the SLC12A3 protein (p.Ser833Thr). This variant is present in population databases (rs146845953, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 22009145). ClinVar contains an entry for this variant (Variation ID: 448393). 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 not expected to disrupt SLC12A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 02, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in the heterozygous state in an individual with Gitelman syndrome, but a second SLC12A3 variant was not identified in this individual (PMID: 22009145); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25841442, 34604727, 22009145) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Uncertain:1

May 09, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.33

.;.;T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.077

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.60

.;.;N;.

PhyloP100

2.2

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.22

T;T;T;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.62

MVP

0.70

MPC

0.080

ClinPred

0.0095

GERP RS

2.9

Varity_R

0.13

gMVP

0.41

Mutation Taster

=7/93

disease causing

(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