rs13306676

Variant names:

• chr16-56887917-C-T
• rs13306676
• NM_001126108.2:c.2179-8C>T

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.2179-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,608,166 control chromosomes in the GnomAD database, including 13,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1085 hom., cov: 28)
  • Exomes 𝑓: 0.13 (12455 hom.)
• Consequence: SLC12A3 NM_001126108.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004880
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.763
• Publications: 7 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=-0.8).
• BP6: Variant 16-56887917-C-T is Benign according to our data. Variant chr16-56887917-C-T is described in ClinVar as Benign. ClinVar VariationId is 255885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 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.2179-8C>T		splice_region intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2179-8C>T		splice_region intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2176-8C>T		splice_region 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.2179-8C>T		splice_region intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2179-8C>T		splice_region intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2176-8C>T		splice_region intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16781 AN: 150388 Hom.: 1085 Cov.: 28

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.0980

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0609

Gnomad SAS AF: 0.0995

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.127 AC: 31836 AN: 250910 AF XY: 0.129

Gnomad AFR exome AF: 0.0511

Gnomad AMR exome AF: 0.0968

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0615

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.128 AC: 186225 AN: 1457674 Hom.: 12455 Cov.: 30 AF XY: 0.128 AC XY: 92773 AN XY: 725314

African (AFR) AF: 0.0483 AC: 1612 AN: 33388

American (AMR) AF: 0.100 AC: 4485 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4594 AN: 26042

East Asian (EAS) AF: 0.0465 AC: 1842 AN: 39606

South Asian (SAS) AF: 0.111 AC: 9607 AN: 86200

European-Finnish (FIN) AF: 0.187 AC: 9879 AN: 52818

Middle Eastern (MID) AF: 0.124 AC: 707 AN: 5710

European-Non Finnish (NFE) AF: 0.132 AC: 145963 AN: 1109114

Other (OTH) AF: 0.125 AC: 7536 AN: 60152

GnomAD4 genome AF: 0.112 AC: 16788 AN: 150492 Hom.: 1085 Cov.: 28 AF XY: 0.114 AC XY: 8341 AN XY: 73382

African (AFR) AF: 0.0512 AC: 2104 AN: 41086

American (AMR) AF: 0.117 AC: 1771 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3460

East Asian (EAS) AF: 0.0607 AC: 310 AN: 5108

South Asian (SAS) AF: 0.0997 AC: 472 AN: 4736

European-Finnish (FIN) AF: 0.183 AC: 1868 AN: 10204

Middle Eastern (MID) AF: 0.159 AC: 46 AN: 290

European-Non Finnish (NFE) AF: 0.137 AC: 9263 AN: 67558

Other (OTH) AF: 0.119 AC: 246 AN: 2074

Alfa AF: 0.130 Hom.: 600

Bravo AF: 0.104

EpiCase AF: 0.139

EpiControl AF: 0.138

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.82
DANN	Benign	0.55
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0
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: rs13306676; hg19: chr16-56921829; COSMIC: COSV52640335;