NM_001126108.2:c.1395C>T

Variant names:

• chr16-56879601-C-T
• rs5801
• NM_001126108.2:c.1395C>T

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.1395C>T​(p.Thr465Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,202 control chromosomes in the GnomAD database, including 16,534 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. T465T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1778 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14756 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.200
• Publications: 19 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-56879601-C-T is Benign according to our data. Variant chr16-56879601-C-T is described in ClinVar as Benign. ClinVar VariationId is 255879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 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.1395C>T	p.Thr465Thr	synonymous	Exon 11 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1395C>T	p.Thr465Thr	synonymous	Exon 11 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1392C>T	p.Thr464Thr	synonymous	Exon 11 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.1395C>T	p.Thr465Thr	synonymous	Exon 11 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1395C>T	p.Thr465Thr	synonymous	Exon 11 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1392C>T	p.Thr464Thr	synonymous	Exon 11 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22817 AN: 151968 Hom.: 1778 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.139 AC: 34943 AN: 251014 AF XY: 0.140

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.0550

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.139 AC: 203569 AN: 1461116 Hom.: 14756 Cov.: 33 AF XY: 0.139 AC XY: 100888 AN XY: 726924

African (AFR) AF: 0.160 AC: 5352 AN: 33470

American (AMR) AF: 0.108 AC: 4826 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4522 AN: 26132

East Asian (EAS) AF: 0.0417 AC: 1655 AN: 39700

South Asian (SAS) AF: 0.115 AC: 9899 AN: 86254

European-Finnish (FIN) AF: 0.192 AC: 10176 AN: 53018

Middle Eastern (MID) AF: 0.119 AC: 687 AN: 5768

European-Non Finnish (NFE) AF: 0.142 AC: 158126 AN: 1111676

Other (OTH) AF: 0.138 AC: 8326 AN: 60380

GnomAD4 genome AF: 0.150 AC: 22830 AN: 152086 Hom.: 1778 Cov.: 32 AF XY: 0.151 AC XY: 11255 AN XY: 74334

African (AFR) AF: 0.162 AC: 6723 AN: 41476

American (AMR) AF: 0.134 AC: 2044 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3472

East Asian (EAS) AF: 0.0557 AC: 288 AN: 5170

South Asian (SAS) AF: 0.108 AC: 519 AN: 4822

European-Finnish (FIN) AF: 0.194 AC: 2053 AN: 10572

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10144 AN: 67986

Other (OTH) AF: 0.144 AC: 303 AN: 2108

Alfa AF: 0.149 Hom.: 6657

Bravo AF: 0.144

Asia WGS AF: 0.133 AC: 462 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.146

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	-0.44
CADD	Benign	8.0
DANN	Benign	0.65
PhyloP100		0.20
Mutation Taster		=98/2	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: rs5801; hg19: chr16-56913513; COSMIC: COSV52632550;