rs2229209

Variant names:

• chr16-56872714-C-T
• rs2229209
• NM_001126108.2:c.1023C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-56872714-C-T
• chr16-56872714-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001126108.2(SLC12A3):​c.1023C>T​(p.Phe341Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,210 control chromosomes in the GnomAD database, including 851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (186 hom., cov: 33)
  • Exomes 𝑓: 0.026 (665 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.64
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-56872714-C-T is Benign according to our data. Variant chr16-56872714-C-T is described in ClinVar as Benign. ClinVar VariationId is 255876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0721 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.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1020C>T	p.Phe340Phe	synonymous	Exon 8 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.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1020C>T	p.Phe340Phe	synonymous	Exon 8 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6316 AN: 152228 Hom.: 186 Cov.: 33

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0485

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0353 AC: 8871 AN: 251464 AF XY: 0.0347

Gnomad AFR exome AF: 0.0696

Gnomad AMR exome AF: 0.0490

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0481

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0262 AC: 38264 AN: 1461864 Hom.: 665 Cov.: 32 AF XY: 0.0269 AC XY: 19586 AN XY: 727232

African (AFR) AF: 0.0737 AC: 2468 AN: 33480

American (AMR) AF: 0.0466 AC: 2084 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 500 AN: 26136

East Asian (EAS) AF: 0.0351 AC: 1393 AN: 39700

South Asian (SAS) AF: 0.0540 AC: 4658 AN: 86258

European-Finnish (FIN) AF: 0.0348 AC: 1857 AN: 53416

Middle Eastern (MID) AF: 0.0215 AC: 124 AN: 5768

European-Non Finnish (NFE) AF: 0.0211 AC: 23456 AN: 1111990

Other (OTH) AF: 0.0285 AC: 1724 AN: 60394

GnomAD4 genome AF: 0.0416 AC: 6332 AN: 152346 Hom.: 186 Cov.: 33 AF XY: 0.0426 AC XY: 3172 AN XY: 74496

African (AFR) AF: 0.0742 AC: 3087 AN: 41578

American (AMR) AF: 0.0495 AC: 757 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.0486 AC: 252 AN: 5182

South Asian (SAS) AF: 0.0509 AC: 246 AN: 4830

European-Finnish (FIN) AF: 0.0363 AC: 386 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1446 AN: 68036

Other (OTH) AF: 0.0359 AC: 76 AN: 2116

Alfa AF: 0.0248 Hom.: 58

Bravo AF: 0.0424

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0225

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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.3
DANN	Benign	0.71
PhyloP100		-1.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2229209; hg19: chr16-56906626; COSMIC: COSV52638820;