rs118121751

Positions:

chr16-56879598-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001126108.2(SLC12A3):c.1392C>A(p.Ala464=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,798 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 29 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.960

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=-0.4).

BP6

Variant 16-56879598-C-A is Benign according to our data. Variant chr16-56879598-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 255878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.96 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00139 (2032/1461554) while in subpopulation EAS AF= 0.0172 (684/39700). AF 95% confidence interval is 0.0162. There are 29 homozygotes in gnomad4_exome. There are 941 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC12A3	NM_001126108.2 linkuse as main transcript	c.1392C>A	p.Ala464=	synonymous_variant	11/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 linkuse as main transcript	c.1392C>A	p.Ala464=	synonymous_variant	11/26		NP_000330.3
SLC12A3	NM_001126107.2 linkuse as main transcript	c.1389C>A	p.Ala463=	synonymous_variant	11/26		NP_001119579.2
SLC12A3	NM_001410896.1 linkuse as main transcript	c.1389C>A	p.Ala463=	synonymous_variant	11/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.1392C>A	p.Ala464=	synonymous_variant	11/26	1	NM_001126108.2	ENSP00000456149	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.1392C>A	p.Ala464=	synonymous_variant	11/26	1		ENSP00000402152	A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.1389C>A	p.Ala463=	synonymous_variant	11/26	1		ENSP00000457552	P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.1389C>A	p.Ala463=	synonymous_variant	11/26	5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

264

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00407

AC:

1021

AN:

251110

Hom.:

AF XY:

0.00335

AC XY:

455

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0108

Gnomad SAS exome

AF:

0.00336

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00139

AC:

2032

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

941

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0172

Gnomad4 SAS exome

AF:

0.00297

Gnomad4 FIN exome

AF:

0.00151

Gnomad4 NFE exome

AF:

0.000164

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152244

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00732

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0112

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00265

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.79

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