16-56887057-C-T

Position:

• chr16-56887057-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001126108.2(SLC12A3):​c.2142C>T​(p.Ala714=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A714A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1169 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8975 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.10

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]

ACMG classification

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/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.2142C>T	p.Ala714=	synonymous_variant	17/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.2142C>T	p.Ala714=	synonymous_variant	17/26
SLC12A3	NM_001126107.2	c.2139C>T	p.Ala713=	synonymous_variant	17/26
SLC12A3	NM_001410896.1	c.2139C>T	p.Ala713=	synonymous_variant	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2142C>T	p.Ala714=	synonymous_variant	17/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.2142C>T	p.Ala714=	synonymous_variant	17/26	1		A1
SLC12A3	ENST00000566786.5	c.2139C>T	p.Ala713=	synonymous_variant	17/26	1		P4
SLC12A3	ENST00000262502.5	c.2139C>T	p.Ala713=	synonymous_variant	17/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17764 AN: 152062 Hom.: 1163 Cov.: 31

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

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.: 34 AF XY: 0.104 AC XY: 75907 AN XY: 727110

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.: 31 AF XY: 0.120 AC XY: 8938 AN XY: 74394

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:9

Revision: criteria provided, multiple submitters, no conflicts

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	Jan 12, 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 specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Other links and lift over

dbSNP: rs5803; hg19: chr16-56920969; COSMIC: COSV52635223;