rs146632606

Variant names:

• chr16-56867150-G-C
• rs146632606
• NM_001126108.2:c.363G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 6P and 5B. PS3 PP2 PP5 BP4 BS2

The NM_001126108.2(SLC12A3):​c.363G>C​(p.Glu121Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000914725: Functional studies in Xenopus oocytes demonstrated proper localization but sodium uptake was significantly reduced compared to wild type (Glaudemans et al. 2012).".

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:8 B:2
• Conservation: PhyloP100: 0.782
• Publications: 7 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: Uncertain_significance. The variant received 1 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000914725: Functional studies in Xenopus oocytes demonstrated proper localization but sodium uptake was significantly reduced compared to wild type (Glaudemans et al. 2012).
• 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 16-56867150-G-C is Pathogenic according to our data. Variant chr16-56867150-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505768.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07202932). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.363G>C	p.Glu121Asp	missense	Exon 2 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.363G>C	p.Glu121Asp	missense	Exon 2 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.360G>C	p.Glu120Asp	missense	Exon 2 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.363G>C	p.Glu121Asp	missense	Exon 2 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.363G>C	p.Glu121Asp	missense	Exon 2 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.360G>C	p.Glu120Asp	missense	Exon 2 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000927 AC: 232 AN: 250226 AF XY: 0.000982

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000898

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00157 AC: 2302 AN: 1461770 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 1074 AN XY: 727172

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000895 AC: 40 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86244

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53360

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00195 AC: 2164 AN: 1111988

Other (OTH) AF: 0.00104 AC: 63 AN: 60388

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74486

African (AFR) AF: 0.000361 AC: 15 AN: 41576

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Familial hypokalemia-hypomagnesemia (5)
1	3	1	not provided (5)
-	2	1	not specified (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	SLC12A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.78
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.22
Sift	Benign	0.19	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.67
MutPred		0.17		Gain of catalytic residue at G123 (P = 0.1393)
MVP		0.86
MPC		0.081
ClinPred		0.013	T
GERP RS		4.7
Varity_R		0.10
gMVP		0.60
Mutation Taster		=87/13	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs146632606; hg19: chr16-56901062;