rs2289119

Variant names:

• chr16-56878991-C-T
• rs2289119
• NM_001126108.2:c.1181-82C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-56878991-C-T
• chr16-56878991-C-G

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.1181-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,506,828 control chromosomes in the GnomAD database, including 28,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2524 hom., cov: 32)
  • Exomes 𝑓: 0.19 (25524 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.975
• Publications: 13 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-56878991-C-T is Benign according to our data. Variant chr16-56878991-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 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.1181-82C>T		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1181-82C>T		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1178-82C>T		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.1181-82C>T		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1181-82C>T		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1178-82C>T		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26942 AN: 152102 Hom.: 2520 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.193 AC: 260995 AN: 1354608 Hom.: 25524 AF XY: 0.194 AC XY: 129936 AN XY: 670716

African (AFR) AF: 0.107 AC: 3306 AN: 30834

American (AMR) AF: 0.267 AC: 9551 AN: 35756

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 4848 AN: 24896

East Asian (EAS) AF: 0.260 AC: 9290 AN: 35782

South Asian (SAS) AF: 0.210 AC: 16458 AN: 78252

European-Finnish (FIN) AF: 0.204 AC: 9762 AN: 47968

Middle Eastern (MID) AF: 0.220 AC: 883 AN: 4010

European-Non Finnish (NFE) AF: 0.188 AC: 195684 AN: 1040664

Other (OTH) AF: 0.199 AC: 11213 AN: 56446

GnomAD4 genome AF: 0.177 AC: 26955 AN: 152220 Hom.: 2524 Cov.: 32 AF XY: 0.181 AC XY: 13493 AN XY: 74408

African (AFR) AF: 0.114 AC: 4736 AN: 41542

American (AMR) AF: 0.248 AC: 3787 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1350 AN: 5174

South Asian (SAS) AF: 0.212 AC: 1023 AN: 4820

European-Finnish (FIN) AF: 0.202 AC: 2135 AN: 10592

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.186 AC: 12634 AN: 68012

Other (OTH) AF: 0.209 AC: 441 AN: 2108

Alfa AF: 0.180 Hom.: 8592

Bravo AF: 0.177

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.47
DANN	Benign	0.46
PhyloP100		-0.97
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2289119;

hg19: chr16-56912903;

COSMIC: COSV52635576;