16-56872714-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001126108.2(SLC12A3):c.1023C>T(p.Phe341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,210 control chromosomes in the GnomAD database, including 851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (186 hom., cov: 33)
  • Exomes 𝑓: 0.026 (665 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.64

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-56872714-C-T is Benign according to our data. Variant chr16-56872714-C-T is described in ClinVar as [Benign]. Clinvar id is 255876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56872714-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1023C>T	p.Phe341=	synonymous_variant	8/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1023C>T	p.Phe341=	synonymous_variant	8/26
SLC12A3	NM_001126107.2	c.1020C>T	p.Phe340=	synonymous_variant	8/26
SLC12A3	NM_001410896.1	c.1020C>T	p.Phe340=	synonymous_variant	8/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1023C>T	p.Phe341=	synonymous_variant	8/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1023C>T	p.Phe341=	synonymous_variant	8/26	1		A1
SLC12A3	ENST00000566786.5	c.1020C>T	p.Phe340=	synonymous_variant	8/26	1		P4
SLC12A3	ENST00000262502.5	c.1020C>T	p.Phe340=	synonymous_variant	8/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6316 AN: 152228 Hom.: 186 Cov.: 33

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0485

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0353 AC: 8871 AN: 251464 Hom.: 193 AF XY: 0.0347 AC XY: 4714 AN XY: 135914

Gnomad AFR exome AF: 0.0696

Gnomad AMR exome AF: 0.0490

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0481

Gnomad SAS exome AF: 0.0545

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0262 AC: 38264 AN: 1461864 Hom.: 665 Cov.: 32 AF XY: 0.0269 AC XY: 19586 AN XY: 727232

Gnomad4 AFR exome AF: 0.0737

Gnomad4 AMR exome AF: 0.0466

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.0351

Gnomad4 SAS exome AF: 0.0540

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0416 AC: 6332 AN: 152346 Hom.: 186 Cov.: 33 AF XY: 0.0426 AC XY: 3172 AN XY: 74496

Gnomad4 AFR AF: 0.0742

Gnomad4 AMR AF: 0.0495

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.0486

Gnomad4 SAS AF: 0.0509

Gnomad4 FIN AF: 0.0363

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0359

Alfa AF: 0.0248 Hom.: 58

Bravo AF: 0.0424

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0225

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:4

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 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	Athena Diagnostics	Jun 29, 2017	- -
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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	2.3
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2229209; hg19: chr16-56906626; COSMIC: COSV52638820;