rs202114767

Variant names:

• chr16-56904402-G-A
• rs202114767
• NM_001126108.2:c.2864G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56904402-G-A
• chr16-56904402-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4

The NM_001126108.2(SLC12A3):​c.2864G>A​(p.Arg955Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005400988: Experimental studies have shown that this missense change affects SLC12A3 function (De Jong JC et. al., 2002)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R955W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.63
• Publications: 12 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]

MIR6863 (HGNC:49942): (microRNA 6863) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005400988: Experimental studies have shown that this missense change affects SLC12A3 function (De Jong JC et. al., 2002).; SCV000932032: Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972).; SCV001879514: Study showed this variant to significantly reduce sodium uptake compared to wild-type (PMID: 12039972).; SCV004033492: PS3:Supporting
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001126108.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56904401-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319919.
• 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 16-56904402-G-A is Pathogenic according to our data. Variant chr16-56904402-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 417864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.357154). . Strength limited to SUPPORTING due to the PP5.

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.2864G>A	p.Arg955Gln	missense	Exon 25 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2891G>A	p.Arg964Gln	missense	Exon 25 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2888G>A	p.Arg963Gln	missense	Exon 25 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.2864G>A	p.Arg955Gln	missense	Exon 25 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2891G>A	p.Arg964Gln	missense	Exon 25 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2888G>A	p.Arg963Gln	missense	Exon 25 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 251492 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85 AN XY: 727120

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26126

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000836 AC: 93 AN: 1111806

Other (OTH) AF: 0.0000994 AC: 6 AN: 60376

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Familial hypokalemia-hypomagnesemia (6)
6	-	-	not provided (6)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.63
MVP		0.96
MPC		0.16
ClinPred		0.27	T
GERP RS		5.4
Varity_R		0.67
gMVP		0.81
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.040		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: rs202114767; hg19: chr16-56938314;