16-56902407-C-T

Variant names:

• chr16-56902407-C-T
• rs12708965
• NM_001126108.2:c.2755C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.2755C>T​(p.Arg919Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,612,492 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts 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. R919H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (144 hom., cov: 31)
  • Exomes 𝑓: 0.018 (479 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.63
• Publications: 38 publications found

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]

SLC12A3 Gene-Disease associations (from GenCC):

• Gitelman syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004836887).
• BP6: Variant 16-56902407-C-T is Benign according to our data. Variant chr16-56902407-C-T is described in ClinVar as Benign. ClinVar VariationId is 319917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2755C>T	p.Arg919Cys	missense_variant	Exon 24 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2782C>T	p.Arg928Cys	missense_variant	Exon 24 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.2779C>T	p.Arg927Cys	missense_variant	Exon 24 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.2752C>T	p.Arg918Cys	missense_variant	Exon 24 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2755C>T	p.Arg919Cys	missense_variant	Exon 24 of 26	1	NM_001126108.2	ENSP00000456149.2

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5305 AN: 151820 Hom.: 145 Cov.: 31

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.0493

Gnomad FIN AF: 0.0320

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0393

GnomAD2 exomes AF: 0.0311 AC: 7811 AN: 251468 AF XY: 0.0303

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.0443

Gnomad ASJ exome AF: 0.0670

Gnomad EAS exome AF: 0.0266

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0183 AC: 26757 AN: 1460554 Hom.: 479 Cov.: 36 AF XY: 0.0191 AC XY: 13876 AN XY: 726546

African (AFR) AF: 0.0728 AC: 2434 AN: 33452

American (AMR) AF: 0.0448 AC: 2003 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 1798 AN: 26088

East Asian (EAS) AF: 0.0227 AC: 900 AN: 39638

South Asian (SAS) AF: 0.0477 AC: 4111 AN: 86238

European-Finnish (FIN) AF: 0.0311 AC: 1660 AN: 53304

Middle Eastern (MID) AF: 0.0493 AC: 284 AN: 5758

European-Non Finnish (NFE) AF: 0.0108 AC: 11979 AN: 1111086

Other (OTH) AF: 0.0263 AC: 1588 AN: 60324

GnomAD4 genome AF: 0.0349 AC: 5308 AN: 151938 Hom.: 144 Cov.: 31 AF XY: 0.0351 AC XY: 2603 AN XY: 74256

African (AFR) AF: 0.0701 AC: 2906 AN: 41426

American (AMR) AF: 0.0385 AC: 588 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3470

East Asian (EAS) AF: 0.0248 AC: 128 AN: 5156

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4824

European-Finnish (FIN) AF: 0.0320 AC: 337 AN: 10526

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 799 AN: 67966

Other (OTH) AF: 0.0389 AC: 82 AN: 2108

Alfa AF: 0.0240 Hom.: 189

Bravo AF: 0.0375

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.0680 AC: 299

ESP6500EA AF: 0.0173 AC: 149

ExAC AF: 0.0306 AC: 3710

Asia WGS AF: 0.0480 AC: 167 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0124

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:6

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg928Cys variant in SLC12A3 has been identified in an individual with Gitelman syndrome (PMID: 9734597). This variant is classified as benign for autosomal recessive Gitelman syndrome because it has been identified in >70% of African chromosomes and 107 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25273610, 17885550, 20981092, 9734597, 27884173, 27535533, 19489442, 31660880, 31398183) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;.;D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D
MetaRNN	Benign	0.0048	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	.;.;M;.
PhyloP100		2.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.035	D;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T
Polyphen		0.53	P;D;D;.
Vest4		0.31
MPC		0.50
ClinPred		0.037	T
GERP RS		4.0
Varity_R		0.53
gMVP		0.80
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12708965; hg19: chr16-56936319; COSMIC: COSV52632562; COSMIC: COSV52632562;