rs2304479

Variant names:

• chr16-56867153-A-G
• rs2304479
• NM_001126108.2:c.366A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-56867153-A-G
• chr16-56867153-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001126108.2(SLC12A3):​c.366A>G​(p.Ala122Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,613,832 control chromosomes in the GnomAD database, including 5,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (576 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4939 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.83
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-56867153-A-G is Benign according to our data. Variant chr16-56867153-A-G is described in ClinVar as Benign. ClinVar VariationId is 255892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 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.366A>G	p.Ala122Ala	synonymous	Exon 2 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.366A>G	p.Ala122Ala	synonymous	Exon 2 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.363A>G	p.Ala121Ala	synonymous	Exon 2 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.366A>G	p.Ala122Ala	synonymous	Exon 2 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.366A>G	p.Ala122Ala	synonymous	Exon 2 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.363A>G	p.Ala121Ala	synonymous	Exon 2 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9394 AN: 152118 Hom.: 578 Cov.: 33

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0521

Gnomad OTH AF: 0.0742

GnomAD2 exomes AF: 0.0963 AC: 24050 AN: 249630 AF XY: 0.0935

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.304

Gnomad FIN exome AF: 0.0463

Gnomad NFE exome AF: 0.0485

Gnomad OTH exome AF: 0.0696

GnomAD4 exome AF: 0.0668 AC: 97585 AN: 1461596 Hom.: 4939 Cov.: 33 AF XY: 0.0684 AC XY: 49702 AN XY: 727092

African (AFR) AF: 0.0193 AC: 646 AN: 33480

American (AMR) AF: 0.195 AC: 8704 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 857 AN: 26122

East Asian (EAS) AF: 0.239 AC: 9490 AN: 39686

South Asian (SAS) AF: 0.124 AC: 10716 AN: 86238

European-Finnish (FIN) AF: 0.0456 AC: 2432 AN: 53348

Middle Eastern (MID) AF: 0.0493 AC: 284 AN: 5766

European-Non Finnish (NFE) AF: 0.0540 AC: 60064 AN: 1111932

Other (OTH) AF: 0.0727 AC: 4392 AN: 60384

GnomAD4 genome AF: 0.0617 AC: 9397 AN: 152236 Hom.: 576 Cov.: 33 AF XY: 0.0662 AC XY: 4927 AN XY: 74438

African (AFR) AF: 0.0199 AC: 828 AN: 41550

American (AMR) AF: 0.136 AC: 2087 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.297 AC: 1531 AN: 5156

South Asian (SAS) AF: 0.124 AC: 600 AN: 4832

European-Finnish (FIN) AF: 0.0441 AC: 468 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0521 AC: 3542 AN: 68010

Other (OTH) AF: 0.0753 AC: 159 AN: 2112

Alfa AF: 0.0553 Hom.: 431

Bravo AF: 0.0677

Asia WGS AF: 0.196 AC: 680 AN: 3478

EpiCase AF: 0.0517

EpiControl AF: 0.0504

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	-0.85
CADD	Benign	2.1
DANN	Benign	0.47
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2304479; hg19: chr16-56901065; COSMIC: COSV52638279;