rs201318038

Positions:

• chr16-56870188-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001126108.2(SLC12A3):​c.694G>A​(p.Ala232Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,864 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A232A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.13

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.694G>A	p.Ala232Thr	missense_variant	5/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.694G>A	p.Ala232Thr	missense_variant	5/26
SLC12A3	NM_001126107.2	c.691G>A	p.Ala231Thr	missense_variant	5/26
SLC12A3	NM_001410896.1	c.691G>A	p.Ala231Thr	missense_variant	5/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.694G>A	p.Ala232Thr	missense_variant	5/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.694G>A	p.Ala232Thr	missense_variant	5/26	1		A1
SLC12A3	ENST00000566786.5	c.691G>A	p.Ala231Thr	missense_variant	5/26	1		P4
SLC12A3	ENST00000262502.5	c.691G>A	p.Ala231Thr	missense_variant	5/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 251220 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000166 AC: 243 AN: 1461620 Hom.: 1 Cov.: 32 AF XY: 0.000219 AC XY: 159 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 21, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 232 of the SLC12A3 protein (p.Ala232Thr). This variant is present in population databases (rs201318038, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of SLC12A3-related conditions (PMID: 24696311). This variant is also known as A230T . ClinVar contains an entry for this variant (Variation ID: 548560). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 21157372). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	D;D;D;D
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.94	P;D;D;.
Vest4		0.96
MVP		0.98
MPC		0.41
ClinPred		0.32	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201318038; hg19: chr16-56904100;