rs2289116

Variant names:

• chr16-56904378-G-A
• rs2289116
• NM_001126108.2:c.2857-17G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56904378-G-A
• chr16-56904378-G-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.2857-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,611,780 control chromosomes in the GnomAD database, including 11,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1550 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9523 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.471
• Publications: 14 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]

MIR6863 (HGNC:49942): (microRNA 6863) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-56904378-G-A is Benign according to our data. Variant chr16-56904378-G-A is described in ClinVar as Benign. ClinVar VariationId is 255890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2857-17G>A		intron_variant	Intron 24 of 25	ENST00000563236.6	NP_001119580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2857-17G>A		intron_variant	Intron 24 of 25	1	NM_001126108.2	ENSP00000456149.2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20447 AN: 152130 Hom.: 1541 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0881

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.122 AC: 30584 AN: 251486 AF XY: 0.117

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.0732

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.112 AC: 162796 AN: 1459532 Hom.: 9523 Cov.: 30 AF XY: 0.111 AC XY: 80410 AN XY: 726176

African (AFR) AF: 0.192 AC: 6402 AN: 33414

American (AMR) AF: 0.177 AC: 7930 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0929 AC: 2426 AN: 26114

East Asian (EAS) AF: 0.0666 AC: 2643 AN: 39664

South Asian (SAS) AF: 0.0928 AC: 8003 AN: 86210

European-Finnish (FIN) AF: 0.123 AC: 6576 AN: 53388

Middle Eastern (MID) AF: 0.142 AC: 817 AN: 5756

European-Non Finnish (NFE) AF: 0.109 AC: 121216 AN: 1110022

Other (OTH) AF: 0.113 AC: 6783 AN: 60258

GnomAD4 genome AF: 0.135 AC: 20485 AN: 152248 Hom.: 1550 Cov.: 32 AF XY: 0.134 AC XY: 10006 AN XY: 74464

African (AFR) AF: 0.191 AC: 7926 AN: 41512

American (AMR) AF: 0.151 AC: 2315 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 306 AN: 3472

East Asian (EAS) AF: 0.0715 AC: 371 AN: 5188

South Asian (SAS) AF: 0.0909 AC: 439 AN: 4828

European-Finnish (FIN) AF: 0.123 AC: 1309 AN: 10614

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7447 AN: 68016

Other (OTH) AF: 0.152 AC: 321 AN: 2116

Alfa AF: 0.120 Hom.: 384

Bravo AF: 0.142

Asia WGS AF: 0.0920 AC: 317 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28008009, 14578305) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hypokalemia-hypomagnesemia Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2289116; hg19: chr16-56938290;