rs146805986

Positions:

• chr16-56880225-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001126108.2(SLC12A3):​c.1539C>T​(p.Tyr513Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,586,306 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (13 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.30

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=-0.51).
• BP6: Variant 16-56880225-C-T is Benign according to our data. Variant chr16-56880225-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56880225-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0054 (823/152348) while in subpopulation AFR AF= 0.0183 (762/41584). AF 95% confidence interval is 0.0172. There are 11 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1539C>T	p.Tyr513Tyr	synonymous_variant	12/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1539C>T	p.Tyr513Tyr	synonymous_variant	12/26		NP_000330.3
SLC12A3	NM_001126107.2	c.1536C>T	p.Tyr512Tyr	synonymous_variant	12/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1536C>T	p.Tyr512Tyr	synonymous_variant	12/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1539C>T	p.Tyr513Tyr	synonymous_variant	12/26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1539C>T	p.Tyr513Tyr	synonymous_variant	12/26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1536C>T	p.Tyr512Tyr	synonymous_variant	12/26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1536C>T	p.Tyr512Tyr	synonymous_variant	12/26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 822 AN: 152230 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00131 AC: 264 AN: 201412 Hom.: 2 AF XY: 0.000944 AC XY: 102 AN XY: 108052

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000623

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000646

Gnomad SAS exome AF: 0.000155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000777

GnomAD4 exome AF: 0.000685 AC: 982 AN: 1433958 Hom.: 13 Cov.: 32 AF XY: 0.000597 AC XY: 424 AN XY: 710618

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.000652

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00540 AC: 823 AN: 152348 Hom.: 11 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74502

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00610

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2019	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.7
DANN	Benign	0.69

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: rs146805986; hg19: chr16-56914137; COSMIC: COSV52635737;