16-56887057-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001126108.2(SLC12A3):c.2142C>T(p.Ala714Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,796 control chromosomes in the GnomAD database, including 10,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1169 hom., cov: 31)

Exomes 𝑓: 0.10 ( 8975 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.10

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 16-56887057-C-T is Benign according to our data. Variant chr16-56887057-C-T is described in ClinVar as [Benign]. Clinvar id is 255884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56887057-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2142C>T	p.Ala714Ala	synonymous_variant	Exon 17 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2142C>T	p.Ala714Ala	synonymous_variant	Exon 17 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2139C>T	p.Ala713Ala	synonymous_variant	Exon 17 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2139C>T	p.Ala713Ala	synonymous_variant	Exon 17 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.2142C>T	p.Ala714Ala	synonymous_variant	Exon 17 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.2142C>T	p.Ala714Ala	synonymous_variant	Exon 17 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.2139C>T	p.Ala713Ala	synonymous_variant	Exon 17 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.2139C>T	p.Ala713Ala	synonymous_variant	Exon 17 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17764

AN:

152062

Hom.:

1163

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.0997

Gnomad EAS

AF:

0.230

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.0934

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0890

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.129

AC:

32336

AN:

251230

Hom.:

2581

AF XY:

0.124

AC XY:

16901

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.220

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.227

Gnomad SAS exome

AF:

0.152

Gnomad FIN exome

AF:

0.0987

Gnomad NFE exome

AF:

0.0875

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.104

AC:

151448

AN:

1461616

Hom.:

8975

Cov.:

AF XY:

0.104

AC XY:

75907

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.124

Gnomad4 AMR exome

AF:

0.218

Gnomad4 ASJ exome

AF:

0.0997

Gnomad4 EAS exome

AF:

0.253

Gnomad4 SAS exome

AF:

0.152

Gnomad4 FIN exome

AF:

0.0962

Gnomad4 NFE exome

AF:

0.0893

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.117

AC:

17785

AN:

152180

Hom.:

1169

Cov.:

AF XY:

0.120

AC XY:

8938

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.128

Gnomad4 AMR

AF:

0.178

Gnomad4 ASJ

AF:

0.0997

Gnomad4 EAS

AF:

0.229

Gnomad4 SAS

AF:

0.158

Gnomad4 FIN

AF:

0.0934

Gnomad4 NFE

AF:

0.0890

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.0968

Hom.:

1032

Bravo

AF:

0.123

Asia WGS

AF:

0.185

AC:

642

AN:

3478

EpiCase

AF:

0.0872

EpiControl

AF:

0.0933

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

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

- -

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. -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided

Benign:3

Sep 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.66

CADD

Benign

0.28

DANN

Benign

0.61

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