rs759426055

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001126108.2(SLC12A3):c.557G>A(p.Gly186Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.99

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 16-56869780-G-A is Pathogenic according to our data. Variant chr16-56869780-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.557G>A	p.Gly186Asp	missense_variant	Exon 4 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.557G>A	p.Gly186Asp	missense_variant	Exon 4 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.554G>A	p.Gly185Asp	missense_variant	Exon 4 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.554G>A	p.Gly185Asp	missense_variant	Exon 4 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.557G>A	p.Gly186Asp	missense_variant	Exon 4 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.557G>A	p.Gly186Asp	missense_variant	Exon 4 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.554G>A	p.Gly185Asp	missense_variant	Exon 4 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.554G>A	p.Gly185Asp	missense_variant	Exon 4 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251386

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000342

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Aug 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 562449). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 25422309, 31672324). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 186 of the SLC12A3 protein (p.Gly186Asp). -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypokalemia-hypomagnesemia

Pathogenic:1

Apr 27, 2022

European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used:PM1, PM2, PM3, PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;.;D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Benign

0.60

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.2

.;M;M;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

0.99

D;D;D;.

Vest4

1.0

MutPred

0.87

.;Loss of glycosylation at S183 (P = 0.0693);Loss of glycosylation at S183 (P = 0.0693);.;

MVP

1.0

MPC

0.18

ClinPred

0.98

GERP RS

4.9

Varity_R

0.91

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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