NM_001126108.2:c.2142C>T

Variant names:

• chr16-56887057-C-T
• rs5803
• NM_001126108.2:c.2142C>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.2142C>T​(p.Ala714Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,796 control chromosomes in the GnomAD database, including 10,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A714A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1169 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8975 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.10
• Publications: 23 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=-0.66).
• BP6: Variant 16-56887057-C-T is Benign according to our data. Variant chr16-56887057-C-T is described in ClinVar as Benign. ClinVar VariationId is 255884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 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.2142C>T	p.Ala714Ala	synonymous	Exon 17 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.2142C>T	p.Ala714Ala	synonymous	Exon 17 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.2139C>T	p.Ala713Ala	synonymous	Exon 17 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.2142C>T	p.Ala714Ala	synonymous	Exon 17 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.2142C>T	p.Ala714Ala	synonymous	Exon 17 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.2139C>T	p.Ala713Ala	synonymous	Exon 17 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17764 AN: 152062 Hom.: 1163 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0934

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0890

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.129 AC: 32336 AN: 251230 AF XY: 0.124

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.0987

Gnomad NFE exome AF: 0.0875

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.104 AC: 151448 AN: 1461616 Hom.: 8975 Cov.: 34 AF XY: 0.104 AC XY: 75907 AN XY: 727110

African (AFR) AF: 0.124 AC: 4159 AN: 33478

American (AMR) AF: 0.218 AC: 9735 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 2606 AN: 26136

East Asian (EAS) AF: 0.253 AC: 10045 AN: 39694

South Asian (SAS) AF: 0.152 AC: 13083 AN: 86252

European-Finnish (FIN) AF: 0.0962 AC: 5119 AN: 53214

Middle Eastern (MID) AF: 0.109 AC: 628 AN: 5768

European-Non Finnish (NFE) AF: 0.0893 AC: 99312 AN: 1111956

Other (OTH) AF: 0.112 AC: 6761 AN: 60394

GnomAD4 genome AF: 0.117 AC: 17785 AN: 152180 Hom.: 1169 Cov.: 31 AF XY: 0.120 AC XY: 8938 AN XY: 74394

African (AFR) AF: 0.128 AC: 5331 AN: 41514

American (AMR) AF: 0.178 AC: 2714 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 346 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1183 AN: 5158

South Asian (SAS) AF: 0.158 AC: 761 AN: 4822

European-Finnish (FIN) AF: 0.0934 AC: 990 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0890 AC: 6050 AN: 68012

Other (OTH) AF: 0.130 AC: 274 AN: 2114

Alfa AF: 0.0997 Hom.: 1516

Bravo AF: 0.123

Asia WGS AF: 0.185 AC: 642 AN: 3478

EpiCase AF: 0.0872

EpiControl AF: 0.0933

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	-0.66
CADD	Benign	0.28
DANN	Benign	0.61
PhyloP100		-4.1
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: rs5803; hg19: chr16-56920969; COSMIC: COSV52635223;