16-56865484-G-T

Variant names:

• chr16-56865484-G-T
• rs76750525
• NM_001126108.2:c.249G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001126108.2(SLC12A3):​c.249G>T​(p.Arg83Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,566 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (30 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.02
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-56865484-G-T is Benign according to our data. Variant chr16-56865484-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255886.
• BP7: Synonymous conserved (PhyloP=3.02 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.249G>T	p.Arg83Arg	synonymous	Exon 1 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.249G>T	p.Arg83Arg	synonymous	Exon 1 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.249G>T	p.Arg83Arg	synonymous	Exon 1 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.249G>T	p.Arg83Arg	synonymous	Exon 1 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.249G>T	p.Arg83Arg	synonymous	Exon 1 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.249G>T	p.Arg83Arg	synonymous	Exon 1 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152212 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00448 AC: 1123 AN: 250570 AF XY: 0.00441

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0205

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00466 AC: 6805 AN: 1461236 Hom.: 30 Cov.: 32 AF XY: 0.00453 AC XY: 3292 AN XY: 726996

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.0191 AC: 1006 AN: 52772

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00493 AC: 5485 AN: 1112008

Other (OTH) AF: 0.00339 AC: 205 AN: 60390

GnomAD4 genome AF: 0.00414 AC: 630 AN: 152330 Hom.: 5 Cov.: 33 AF XY: 0.00454 AC XY: 338 AN XY: 74488

African (AFR) AF: 0.000770 AC: 32 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0222 AC: 236 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00495 AC: 337 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00374 Hom.: 0

Bravo AF: 0.00244

EpiCase AF: 0.00311

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Familial hypokalemia-hypomagnesemia (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		3.0
PromoterAI		0.0027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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: rs76750525; hg19: chr16-56899396; COSMIC: COSV52636381;