rs61730207

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001126108.2(SLC12A3):c.2273T>C(p.Ile758Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000229 in 1,609,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.16

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2703361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 linkuse as main transcript	c.2273T>C	p.Ile758Thr	missense_variant	18/26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 linkuse as main transcript	c.2273T>C	p.Ile758Thr	missense_variant	18/26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2270T>C	p.Ile757Thr	missense_variant	18/26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2270T>C	p.Ile757Thr	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.2273T>C	p.Ile758Thr	missense_variant	18/26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.2273T>C	p.Ile758Thr	missense_variant	18/26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.2270T>C	p.Ile757Thr	missense_variant	18/26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.2270T>C	p.Ile757Thr	missense_variant	18/26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000280

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251152

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000868

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:

0.000388

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000240

AC:

350

AN:

1457506

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

173

AN XY:

725364

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000125

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000280

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Nov 11, 2021	PP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2022	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 758 of the SLC12A3 protein (p.Ile758Thr). This variant is present in population databases (rs61730207, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SLC12A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1343265). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

.;.;D;D

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;D;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.4

.;M;M;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.12

B;P;B;.

Vest4

0.36

MVP

0.98

MPC

0.11

ClinPred

0.10

GERP RS

4.7

Varity_R

0.45

gMVP

0.71

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