rs775931992

Variant names:

• chr16-56879087-C-G
• rs775931992
• NM_001126108.2:c.1195C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-56879087-C-G
• chr16-56879087-C-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001126108.2(SLC12A3):​c.1195C>G​(p.Arg399Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R399H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.73
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56879088-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1489260.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 16-56879087-C-G is Pathogenic according to our data. Variant chr16-56879087-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2826924.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1195C>G	p.Arg399Gly	missense_variant	Exon 10 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1195C>G	p.Arg399Gly	missense_variant	Exon 10 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.1192C>G	p.Arg398Gly	missense_variant	Exon 10 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1192C>G	p.Arg398Gly	missense_variant	Exon 10 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1195C>G	p.Arg399Gly	missense_variant	Exon 10 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1195C>G	p.Arg399Gly	missense_variant	Exon 10 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1192C>G	p.Arg398Gly	missense_variant	Exon 10 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1192C>G	p.Arg398Gly	missense_variant	Exon 10 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Arg399 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18391953, 23328711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with SLC12A3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 399 of the SLC12A3 protein (p.Arg399Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;.;D;D
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.7	.;H;H;.
PhyloP100		3.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.97	D;D;D;.
Vest4		0.89
MutPred		0.75		.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.96
MPC		0.50
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.98

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

Other links and lift over

dbSNP: rs775931992; hg19: chr16-56912999;