16-56879601-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001126108.2(SLC12A3):c.1395C>T(p.Thr465Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,202 control chromosomes in the GnomAD database, including 16,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1778 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14756 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.200

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 16-56879601-C-T is Benign according to our data. Variant chr16-56879601-C-T is described in ClinVar as [Benign]. Clinvar id is 255879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56879601-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.1395C>T	p.Thr465Thr	synonymous_variant	Exon 11 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.1395C>T	p.Thr465Thr	synonymous_variant	Exon 11 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.1392C>T	p.Thr464Thr	synonymous_variant	Exon 11 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.1392C>T	p.Thr464Thr	synonymous_variant	Exon 11 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.1395C>T	p.Thr465Thr	synonymous_variant	Exon 11 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.1395C>T	p.Thr465Thr	synonymous_variant	Exon 11 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.1392C>T	p.Thr464Thr	synonymous_variant	Exon 11 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.1392C>T	p.Thr464Thr	synonymous_variant	Exon 11 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22817

AN:

151968

Hom.:

1778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.0560

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.149

Gnomad OTH

AF:

0.141

GnomAD3 exomes

AF:

0.139

AC:

34943

AN:

251014

Hom.:

2644

AF XY:

0.140

AC XY:

18953

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.0550

Gnomad SAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.189

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.139

AC:

203569

AN:

1461116

Hom.:

14756

Cov.:

AF XY:

0.139

AC XY:

100888

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.160

Gnomad4 AMR exome

AF:

0.108

Gnomad4 ASJ exome

AF:

0.173

Gnomad4 EAS exome

AF:

0.0417

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.192

Gnomad4 NFE exome

AF:

0.142

Gnomad4 OTH exome

AF:

0.138

GnomAD4 genome

AF:

0.150

AC:

22830

AN:

152086

Hom.:

1778

Cov.:

AF XY:

0.151

AC XY:

11255

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.162

Gnomad4 AMR

AF:

0.134

Gnomad4 ASJ

AF:

0.177

Gnomad4 EAS

AF:

0.0557

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.194

Gnomad4 NFE

AF:

0.149

Gnomad4 OTH

AF:

0.144

Alfa

AF:

0.149

Hom.:

3419

Bravo

AF:

0.144

Asia WGS

AF:

0.133

AC:

462

AN:

3478

EpiCase

AF:

0.149

EpiControl

AF:

0.146

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.0

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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