rs5804

Variant names:

• chr16-56894607-C-T
• rs5804
• NM_001126108.2:c.2598C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.2598C>T​(p.Gly866Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,402 control chromosomes in the GnomAD database, including 9,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (890 hom., cov: 31)
  • Exomes 𝑓: 0.10 (9063 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.55
• Publications: 25 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-56894607-C-T is Benign according to our data. Variant chr16-56894607-C-T is described in ClinVar as Benign. ClinVar VariationId is 255887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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.2598C>T	p.Gly866Gly	synonymous	Exon 22 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2625C>T	p.Gly875Gly	synonymous	Exon 22 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2622C>T	p.Gly874Gly	synonymous	Exon 22 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.2598C>T	p.Gly866Gly	synonymous	Exon 22 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2625C>T	p.Gly875Gly	synonymous	Exon 22 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2622C>T	p.Gly874Gly	synonymous	Exon 22 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0964 AC: 14652 AN: 151988 Hom.: 885 Cov.: 31

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0913

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.126 AC: 31608 AN: 251316 AF XY: 0.123

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.0986

Gnomad NFE exome AF: 0.0897

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.104 AC: 151924 AN: 1461296 Hom.: 9063 Cov.: 32 AF XY: 0.105 AC XY: 76383 AN XY: 726972

African (AFR) AF: 0.0435 AC: 1456 AN: 33472

American (AMR) AF: 0.216 AC: 9664 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3519 AN: 26120

East Asian (EAS) AF: 0.252 AC: 10019 AN: 39684

South Asian (SAS) AF: 0.153 AC: 13223 AN: 86210

European-Finnish (FIN) AF: 0.0962 AC: 5140 AN: 53408

Middle Eastern (MID) AF: 0.106 AC: 610 AN: 5768

European-Non Finnish (NFE) AF: 0.0914 AC: 101574 AN: 1111546

Other (OTH) AF: 0.111 AC: 6719 AN: 60376

GnomAD4 genome AF: 0.0964 AC: 14664 AN: 152106 Hom.: 890 Cov.: 31 AF XY: 0.101 AC XY: 7476 AN XY: 74342

African (AFR) AF: 0.0493 AC: 2047 AN: 41496

American (AMR) AF: 0.171 AC: 2617 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 476 AN: 3466

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5162

South Asian (SAS) AF: 0.160 AC: 773 AN: 4818

European-Finnish (FIN) AF: 0.0933 AC: 989 AN: 10598

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0913 AC: 6206 AN: 67978

Other (OTH) AF: 0.110 AC: 231 AN: 2106

Alfa AF: 0.0953 Hom.: 634

Bravo AF: 0.0997

Asia WGS AF: 0.184 AC: 637 AN: 3478

EpiCase AF: 0.0916

EpiControl AF: 0.0953

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial hypokalemia-hypomagnesemia (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.0
DANN	Benign	0.63
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5804; hg19: chr16-56928519; COSMIC: COSV52635248;