rs759532318

chr16-56879108-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001126108.2(SLC12A3):c.1216A>C(p.Asn406His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.78

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 5 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity S12A3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-56879108-A-C is Pathogenic according to our data. Variant chr16-56879108-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225467.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1216A>C	p.Asn406His	missense_variant	10/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1216A>C	p.Asn406His	missense_variant	10/26
SLC12A3	NM_001126107.2	c.1213A>C	p.Asn405His	missense_variant	10/26
SLC12A3	NM_001410896.1	c.1213A>C	p.Asn405His	missense_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1216A>C	p.Asn406His	missense_variant	10/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1216A>C	p.Asn406His	missense_variant	10/26	1		A1
SLC12A3	ENST00000566786.5	c.1213A>C	p.Asn405His	missense_variant	10/26	1		P4
SLC12A3	ENST00000262502.5	c.1213A>C	p.Asn405His	missense_variant	10/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000841 AC: 21 AN: 249840 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461156 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 726838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00103

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 406 of the SLC12A3 protein (p.Asn406His). This variant is present in population databases (rs759532318, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 14655226, 17511264, 26770037, 30596175, 32528714). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225467). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Familial hypokalemia-hypomagnesemia Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	-0.040	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.92
MutPred		0.69		.;Gain of catalytic residue at N406 (P = 0.0613);Gain of catalytic residue at N406 (P = 0.0613);.;
MVP		0.98
MPC		0.45
ClinPred		0.57	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs759532318; hg19: chr16-56913020;