NM_001126108.2:c.1884G>A

Variant names:

• chr16-56885323-G-A
• rs5802
• NM_001126108.2:c.1884G>A

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.1884G>A​(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0933 in 1,555,250 control chromosomes in the GnomAD database, including 7,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (616 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6552 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -6.14
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-56885323-G-A is Benign according to our data. Variant chr16-56885323-G-A is described in ClinVar as Benign. ClinVar VariationId is 255883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0976 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.1884G>A	p.Ser628Ser	synonymous	Exon 15 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1884G>A	p.Ser628Ser	synonymous	Exon 15 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1881G>A	p.Ser627Ser	synonymous	Exon 15 of 26	NP_001119579.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1884G>A	p.Ser628Ser	synonymous	Exon 15 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1884G>A	p.Ser628Ser	synonymous	Exon 15 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1881G>A	p.Ser627Ser	synonymous	Exon 15 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12287 AN: 152112 Hom.: 614 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.0986

GnomAD2 exomes AF: 0.0854 AC: 13926 AN: 163130 AF XY: 0.0872

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.0875

Gnomad EAS exome AF: 0.0510

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0947 AC: 132878 AN: 1403020 Hom.: 6552 Cov.: 31 AF XY: 0.0948 AC XY: 65660 AN XY: 692444

African (AFR) AF: 0.0431 AC: 1373 AN: 31846

American (AMR) AF: 0.0577 AC: 2093 AN: 36248

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 2243 AN: 25192

East Asian (EAS) AF: 0.0331 AC: 1200 AN: 36204

South Asian (SAS) AF: 0.0771 AC: 6123 AN: 79400

European-Finnish (FIN) AF: 0.124 AC: 6164 AN: 49512

Middle Eastern (MID) AF: 0.130 AC: 741 AN: 5702

European-Non Finnish (NFE) AF: 0.0995 AC: 107558 AN: 1080760

Other (OTH) AF: 0.0926 AC: 5383 AN: 58156

GnomAD4 genome AF: 0.0808 AC: 12298 AN: 152230 Hom.: 616 Cov.: 32 AF XY: 0.0817 AC XY: 6081 AN XY: 74420

African (AFR) AF: 0.0445 AC: 1849 AN: 41540

American (AMR) AF: 0.0767 AC: 1173 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3468

East Asian (EAS) AF: 0.0484 AC: 251 AN: 5190

South Asian (SAS) AF: 0.0759 AC: 366 AN: 4824

European-Finnish (FIN) AF: 0.126 AC: 1340 AN: 10596

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0996 AC: 6772 AN: 68004

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.0901 Hom.: 758

Bravo AF: 0.0752

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	0.32
DANN	Benign	0.38
PhyloP100		-6.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs5802; hg19: chr16-56919235; COSMIC: COSV108062382;