rs11643718

Positions:

chr16-56899607-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.2711G>A(p.Arg904Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,514 control chromosomes in the GnomAD database, including 9,371 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 Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 737 hom., cov: 33)

Exomes 𝑓: 0.11 ( 8634 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.30

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=0.0014933348).

BP6

Variant 16-56899607-G-A is Benign according to our data. Variant chr16-56899607-G-A is described in ClinVar as [Benign]. Clinvar id is 255888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56899607-G-A is described in Lovd as [Benign]. Variant chr16-56899607-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC12A3	NM_001126108.2 linkuse as main transcript	c.2711G>A	p.Arg904Gln	missense_variant	23/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 linkuse as main transcript	c.2738G>A	p.Arg913Gln	missense_variant	23/26		NP_000330.3
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2735G>A	p.Arg912Gln	missense_variant	23/26		NP_001119579.2
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2708G>A	p.Arg903Gln	missense_variant	23/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.2711G>A	p.Arg904Gln	missense_variant	23/26	1	NM_001126108.2	ENSP00000456149	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.2738G>A	p.Arg913Gln	missense_variant	23/26	1		ENSP00000402152	A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.2735G>A	p.Arg912Gln	missense_variant	23/26	1		ENSP00000457552	P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.2708G>A	p.Arg903Gln	missense_variant	23/26	5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes

AF:

0.0854

AC:

12997

AN:

152170

Hom.:

736

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.0859

Gnomad EAS

AF:

0.0741

Gnomad SAS

AF:

0.0909

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.109

AC:

27318

AN:

251438

Hom.:

1652

AF XY:

0.108

AC XY:

14702

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.0870

Gnomad EAS exome

AF:

0.0756

Gnomad SAS exome

AF:

0.0945

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.106

AC:

155243

AN:

1460226

Hom.:

8634

Cov.:

AF XY:

0.106

AC XY:

77237

AN XY:

726526

show subpopulations

Gnomad4 AFR exome

AF:

0.0185

Gnomad4 AMR exome

AF:

0.166

Gnomad4 ASJ exome

AF:

0.0886

Gnomad4 EAS exome

AF:

0.0679

Gnomad4 SAS exome

AF:

0.0933

Gnomad4 FIN exome

AF:

0.126

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0853

AC:

12996

AN:

152288

Hom.:

737

Cov.:

AF XY:

0.0875

AC XY:

6511

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0213

Gnomad4 AMR

AF:

0.129

Gnomad4 ASJ

AF:

0.0859

Gnomad4 EAS

AF:

0.0745

Gnomad4 SAS

AF:

0.0909

Gnomad4 FIN

AF:

0.127

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.107

Alfa

AF:

0.107

Hom.:

2505

Bravo

AF:

0.0850

TwinsUK

AF:

0.112

AC:

417

ALSPAC

AF:

0.105

AC:

406

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.104

AC:

894

ExAC

AF:

0.103

AC:

12563

Asia WGS

AF:

0.0830

AC:

289

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.118

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	This variant is associated with the following publications: (PMID: 25401745, 24776766, 15480096, 9734597, 10988270, 28008009, 28744814, 32292023, 31398183) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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

0.073

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.43

DEOGEN2

Benign

0.17

.;.;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.73

T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

.;.;N;.

MutationTaster

Benign

0.99

P;P;P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

0.51

N;N;N;N

REVEL

Benign

0.015

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.85

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.076

MPC

0.10

ClinPred

0.0022

GERP RS

1.7

Varity_R

0.051

gMVP

0.42

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