rs34772420

Variant names:

• chr16-56902360-T-C
• rs34772420
• NM_001126108.2:c.2721-13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.2721-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,760 control chromosomes in the GnomAD database, including 15,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2850 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13108 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.477
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-56902360-T-C is Benign according to our data. Variant chr16-56902360-T-C is described in ClinVar as Benign. ClinVar VariationId is 255889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 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.2721-13T>C		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2748-13T>C		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2745-13T>C		intron	N/A	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.2721-13T>C		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2748-13T>C		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2745-13T>C		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26554 AN: 152006 Hom.: 2844 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.131 AC: 33002 AN: 251386 AF XY: 0.130

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.0742

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0353

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.128 AC: 187541 AN: 1461636 Hom.: 13108 Cov.: 35 AF XY: 0.128 AC XY: 92728 AN XY: 727114

African (AFR) AF: 0.309 AC: 10341 AN: 33476

American (AMR) AF: 0.0775 AC: 3466 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3981 AN: 26130

East Asian (EAS) AF: 0.0232 AC: 922 AN: 39700

South Asian (SAS) AF: 0.110 AC: 9476 AN: 86254

European-Finnish (FIN) AF: 0.148 AC: 7920 AN: 53382

Middle Eastern (MID) AF: 0.132 AC: 759 AN: 5760

European-Non Finnish (NFE) AF: 0.128 AC: 142628 AN: 1111832

Other (OTH) AF: 0.133 AC: 8048 AN: 60386

GnomAD4 genome AF: 0.175 AC: 26584 AN: 152124 Hom.: 2850 Cov.: 31 AF XY: 0.173 AC XY: 12829 AN XY: 74368

African (AFR) AF: 0.298 AC: 12373 AN: 41456

American (AMR) AF: 0.118 AC: 1806 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 539 AN: 3468

East Asian (EAS) AF: 0.0390 AC: 202 AN: 5178

South Asian (SAS) AF: 0.100 AC: 483 AN: 4826

European-Finnish (FIN) AF: 0.147 AC: 1555 AN: 10590

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9122 AN: 67990

Other (OTH) AF: 0.168 AC: 354 AN: 2112

Alfa AF: 0.175 Hom.: 510

Bravo AF: 0.177

Asia WGS AF: 0.127 AC: 440 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Familial hypokalemia-hypomagnesemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.30
PhyloP100		-0.48
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: rs34772420; hg19: chr16-56936272; COSMIC: COSV52637376; COSMIC: COSV52637376;