NM_001126108.2:c.2221G>A

Variant names:

• chr16-56887967-G-A
• rs138977195
• NM_001126108.2:c.2221G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PP2 PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.2221G>A​(p.Gly741Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,612,942 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000398133: Functional studies in Xenopus oocytes demonstrated that the p.Gly741Arg variant resulted in no sodium ion uptake activity, showed intracellular localization rather than plasma membrane localization compared to wild type, and was not glycosylated (De Jong et al. 2002)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00080 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29
• Conservation: PhyloP100: 9.83
• Publications: 31 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000398133: Functional studies in Xenopus oocytes demonstrated that the p.Gly741Arg variant resulted in no sodium ion uptake activity, showed intracellular localization rather than plasma membrane localization compared to wild type, and was not glycosylated (De Jong et al. 2002).; SCV004046307: Functional studies have shown that this change results in reduced sodium uptake (PMID: 12039972).; SCV004175306: Functional studies show that the variant results in a non-functional protein (PMID:12039972)(PS3).; SCV006582436: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12039972)."; SCV000321949: "In vitro functional analysis demonstrated significantly diminished metolazone-sensitive sodium uptake levels in cells harboring this variant; immunocytochemical analysis revealed that the altered protein was predominantly localized to the cytoplasm rather than the plasma membrane as observed with the wild-type protein (De Jong et al., 2002);"; SCV000931547: Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972).; SCV001879513: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12039972); SCV005414351: PS3_supporting; SCV004105941: Functional studies indicate that the p.Gly741Arg change impacts protein function (De Jong et al. 2002. PubMed ID: 12039972).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001126108.2
• 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.
• PP5: Variant 16-56887967-G-A is Pathogenic according to our data. Variant chr16-56887967-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2221G>A	p.Gly741Arg	missense	Exon 18 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2221G>A	p.Gly741Arg	missense	Exon 18 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2218G>A	p.Gly740Arg	missense	Exon 18 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.2221G>A	p.Gly741Arg	missense	Exon 18 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2221G>A	p.Gly741Arg	missense	Exon 18 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2218G>A	p.Gly740Arg	missense	Exon 18 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 151816 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251298 AF XY: 0.000346

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000802 AC: 1171 AN: 1461010 Hom.: 0 Cov.: 31 AF XY: 0.000788 AC XY: 573 AN XY: 726842

African (AFR) AF: 0.000120 AC: 4 AN: 33458

American (AMR) AF: 0.000313 AC: 14 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00101 AC: 1120 AN: 1111488

Other (OTH) AF: 0.000348 AC: 21 AN: 60340

GnomAD4 genome AF: 0.000408 AC: 62 AN: 151932 Hom.: 0 Cov.: 30 AF XY: 0.000390 AC XY: 29 AN XY: 74276

African (AFR) AF: 0.000121 AC: 5 AN: 41418

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000795 AC: 54 AN: 67966

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000382

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Familial hypokalemia-hypomagnesemia (15)
9	-	-	not provided (9)
1	-	-	Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia (1)
1	-	-	Hypokalemia;C0151786:Muscle weakness;C0231528:Myalgia;C1522135:Hypermagnesemia (1)
1	-	-	Inherited renal tubular disease (1)
1	-	-	Renal tubulopathies (1)
1	-	-	SLC12A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.89		Gain of MoRF binding (P = 0.0166)
MVP		0.96
MPC		0.52
ClinPred		0.37	T
GERP RS		3.7
Varity_R		0.94
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs138977195; hg19: chr16-56921879;