rs11643718

chr16-56899607-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):c.2711G>A(p.Arg904Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,514 control chromosomes in the GnomAD database, including 9,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R904W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.085 (737 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8634 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.30

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014933348).
• BP6: Variant 16-56899607-G-A is Benign according to our data. Variant chr16-56899607-G-A is described in ClinVar as [Benign]. Clinvar id is 255888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56899607-G-A is described in Lovd as [Benign]. Variant chr16-56899607-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.2711G>A	p.Arg904Gln	missense_variant	23/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.2738G>A	p.Arg913Gln	missense_variant	23/26
SLC12A3	NM_001126107.2	c.2735G>A	p.Arg912Gln	missense_variant	23/26
SLC12A3	NM_001410896.1	c.2708G>A	p.Arg903Gln	missense_variant	23/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2711G>A	p.Arg904Gln	missense_variant	23/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.2738G>A	p.Arg913Gln	missense_variant	23/26	1		A1
SLC12A3	ENST00000566786.5	c.2735G>A	p.Arg912Gln	missense_variant	23/26	1		P4
SLC12A3	ENST00000262502.5	c.2708G>A	p.Arg903Gln	missense_variant	23/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12997 AN: 152170 Hom.: 736 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.109 AC: 27318 AN: 251438 Hom.: 1652 AF XY: 0.108 AC XY: 14702 AN XY: 135898

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.0870

Gnomad EAS exome AF: 0.0756

Gnomad SAS exome AF: 0.0945

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.106 AC: 155243 AN: 1460226 Hom.: 8634 Cov.: 31 AF XY: 0.106 AC XY: 77237 AN XY: 726526

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.0886

Gnomad4 EAS exome AF: 0.0679

Gnomad4 SAS exome AF: 0.0933

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.0853 AC: 12996 AN: 152288 Hom.: 737 Cov.: 33 AF XY: 0.0875 AC XY: 6511 AN XY: 74450

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.0859

Gnomad4 EAS AF: 0.0745

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.107

Alfa AF: 0.107 Hom.: 2505

Bravo AF: 0.0850

TwinsUK AF: 0.112 AC: 417

ALSPAC AF: 0.105 AC: 406

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.104 AC: 894

ExAC AF: 0.103 AC: 12563

Asia WGS AF: 0.0830 AC: 289 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.118

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	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	This variant is associated with the following publications: (PMID: 25401745, 24776766, 15480096, 9734597, 10988270, 28008009, 28744814, 32292023, 31398183) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	18
Dann	Benign	0.43
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.51	N;N;N;N
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.076
MPC		0.10
ClinPred		0.0022	T
GERP RS		1.7
Varity_R		0.051
gMVP		0.42

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: rs11643718; hg19: chr16-56933519; COSMIC: COSV52639281; COSMIC: COSV52639281;