16-56885323-G-A

Position:

• chr16-56885323-G-A

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.1884G>A​(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0933 in 1,555,250 control chromosomes in the GnomAD database, including 7,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (616 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6552 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -6.14

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=-0.87).
• BP6: Variant 16-56885323-G-A is Benign according to our data. Variant chr16-56885323-G-A is described in ClinVar as [Benign]. Clinvar id is 255883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56885323-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1884G>A	p.Ser628Ser	synonymous_variant	15/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1884G>A	p.Ser628Ser	synonymous_variant	15/26		NP_000330.3
SLC12A3	NM_001126107.2	c.1881G>A	p.Ser627Ser	synonymous_variant	15/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1881G>A	p.Ser627Ser	synonymous_variant	15/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1884G>A	p.Ser628Ser	synonymous_variant	15/26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1884G>A	p.Ser628Ser	synonymous_variant	15/26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1881G>A	p.Ser627Ser	synonymous_variant	15/26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1881G>A	p.Ser627Ser	synonymous_variant	15/26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12287 AN: 152112 Hom.: 614 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.0986

GnomAD3 exomes AF: 0.0854 AC: 13926 AN: 163130 Hom.: 635 AF XY: 0.0872 AC XY: 7509 AN XY: 86108

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.0875

Gnomad EAS exome AF: 0.0510

Gnomad SAS exome AF: 0.0771

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0947 AC: 132878 AN: 1403020 Hom.: 6552 Cov.: 31 AF XY: 0.0948 AC XY: 65660 AN XY: 692444

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.0890

Gnomad4 EAS exome AF: 0.0331

Gnomad4 SAS exome AF: 0.0771

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0995

Gnomad4 OTH exome AF: 0.0926

GnomAD4 genome AF: 0.0808 AC: 12298 AN: 152230 Hom.: 616 Cov.: 32 AF XY: 0.0817 AC XY: 6081 AN XY: 74420

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.0767

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0484

Gnomad4 SAS AF: 0.0759

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.0996

Gnomad4 OTH AF: 0.0975

Alfa AF: 0.0929 Hom.: 598

Bravo AF: 0.0752

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5802; hg19: chr16-56919235;