rs11643718

Variant names:

• chr16-56899607-G-A
• rs11643718
• NM_001126108.2:c.2711G>A

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.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. 16/21 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:10
• Conservation: PhyloP100: 1.30
• Publications: 84 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: PanelApp Australia, 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=0.0014933348).
• BP6: Variant 16-56899607-G-A is Benign according to our data. Variant chr16-56899607-G-A is described in ClinVar as Benign. ClinVar VariationId is 255888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.2711G>A	p.Arg904Gln	missense	Exon 23 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2738G>A	p.Arg913Gln	missense	Exon 23 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2735G>A	p.Arg912Gln	missense	Exon 23 of 26	NP_001119579.2	P55017-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.2711G>A	p.Arg904Gln	missense	Exon 23 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2738G>A	p.Arg913Gln	missense	Exon 23 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2735G>A	p.Arg912Gln	missense	Exon 23 of 26	ENSP00000457552.1	P55017-3

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

GnomAD2 exomes AF: 0.109 AC: 27318 AN: 251438 AF XY: 0.108

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 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

African (AFR) AF: 0.0185 AC: 618 AN: 33446

American (AMR) AF: 0.166 AC: 7413 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0886 AC: 2314 AN: 26126

East Asian (EAS) AF: 0.0679 AC: 2693 AN: 39690

South Asian (SAS) AF: 0.0933 AC: 8049 AN: 86228

European-Finnish (FIN) AF: 0.126 AC: 6719 AN: 53406

Middle Eastern (MID) AF: 0.132 AC: 763 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 120606 AN: 1110492

Other (OTH) AF: 0.101 AC: 6068 AN: 60350

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

African (AFR) AF: 0.0213 AC: 886 AN: 41580

American (AMR) AF: 0.129 AC: 1972 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0859 AC: 298 AN: 3470

East Asian (EAS) AF: 0.0745 AC: 386 AN: 5184

South Asian (SAS) AF: 0.0909 AC: 439 AN: 4828

European-Finnish (FIN) AF: 0.127 AC: 1345 AN: 10588

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7398 AN: 68022

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.103 Hom.: 3412

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial hypokalemia-hypomagnesemia (4)
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.076
MPC		0.10
ClinPred		0.0022	T
GERP RS		1.7
Varity_R		0.051
gMVP		0.42
Mutation Taster		=100/0	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: rs11643718; hg19: chr16-56933519; COSMIC: COSV52639281; COSMIC: COSV52639281;