rs886039754

chr16-56885358-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001126108.2(SLC12A3):c.1919A>G(p.Asn640Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,397,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.27

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 Likely_pathogenic. Variant got 7 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, 2 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 16-56885358-A-G is Pathogenic according to our data. Variant chr16-56885358-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 267286.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1919A>G	p.Asn640Ser	missense_variant	15/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1919A>G	p.Asn640Ser	missense_variant	15/26
SLC12A3	NM_001126107.2	c.1916A>G	p.Asn639Ser	missense_variant	15/26
SLC12A3	NM_001410896.1	c.1916A>G	p.Asn639Ser	missense_variant	15/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1919A>G	p.Asn640Ser	missense_variant	15/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1919A>G	p.Asn640Ser	missense_variant	15/26	1		A1
SLC12A3	ENST00000566786.5	c.1916A>G	p.Asn639Ser	missense_variant	15/26	1		P4
SLC12A3	ENST00000262502.5	c.1916A>G	p.Asn639Ser	missense_variant	15/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000125 AC: 2 AN: 159468 Hom.: 0 AF XY: 0.0000119 AC XY: 1 AN XY: 83970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000865

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1397082 Hom.: 0 Cov.: 29 AF XY: 0.00000290 AC XY: 2 AN XY: 689644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000279

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Endocrinology, Sir Run Run Shaw Hospital	Jan 01, 2016	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2023

This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 29378538, 33095447). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 640 of the SLC12A3 protein (p.Asn640Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. ClinVar contains an entry for this variant (Variation ID: 267286). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.98	D;D;D;.
Vest4		0.96
MutPred		0.73		.;Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);.;
MVP		0.99
MPC		0.42
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886039754; hg19: chr16-56919270;