rs2278489

Variant names:

• chr16-56892916-T-A
• rs2278489
• NM_001126108.2:c.2420-37T>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56892916-T-A
• chr16-56892916-T-C
• chr16-56892916-T-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.2420-37T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,569,074 control chromosomes in the GnomAD database, including 9,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1616 hom., cov: 35)
  • Exomes 𝑓: 0.10 (8290 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.987
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-56892916-T-A is Benign according to our data. Variant chr16-56892916-T-A is described in ClinVar as Benign. ClinVar VariationId is 1182000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2420-37T>A		intron_variant	Intron 20 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2447-37T>A		intron_variant	Intron 20 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.2444-37T>A		intron_variant	Intron 20 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.2417-37T>A		intron_variant	Intron 20 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2420-37T>A		intron_variant	Intron 20 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2447-37T>A		intron_variant	Intron 20 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2444-37T>A		intron_variant	Intron 20 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2417-37T>A		intron_variant	Intron 20 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20253 AN: 152162 Hom.: 1609 Cov.: 35

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.103 AC: 24829 AN: 240136 AF XY: 0.104

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.0921

Gnomad EAS exome AF: 0.0484

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.105 AC: 148654 AN: 1416794 Hom.: 8290 Cov.: 23 AF XY: 0.105 AC XY: 74001 AN XY: 707094

African (AFR) AF: 0.207 AC: 6745 AN: 32538

American (AMR) AF: 0.0725 AC: 3198 AN: 44084

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 2401 AN: 25778

East Asian (EAS) AF: 0.0327 AC: 1288 AN: 39338

South Asian (SAS) AF: 0.0902 AC: 7662 AN: 84912

European-Finnish (FIN) AF: 0.126 AC: 6663 AN: 52978

Middle Eastern (MID) AF: 0.152 AC: 854 AN: 5608

European-Non Finnish (NFE) AF: 0.106 AC: 113411 AN: 1072762

Other (OTH) AF: 0.109 AC: 6432 AN: 58796

GnomAD4 genome AF: 0.133 AC: 20274 AN: 152280 Hom.: 1616 Cov.: 35 AF XY: 0.133 AC XY: 9868 AN XY: 74438

African (AFR) AF: 0.209 AC: 8707 AN: 41566

American (AMR) AF: 0.106 AC: 1624 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3472

East Asian (EAS) AF: 0.0456 AC: 236 AN: 5174

South Asian (SAS) AF: 0.0877 AC: 423 AN: 4824

European-Finnish (FIN) AF: 0.127 AC: 1352 AN: 10610

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7289 AN: 68012

Other (OTH) AF: 0.136 AC: 288 AN: 2110

Alfa AF: 0.0982 Hom.: 2226

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.37
DANN	Benign	0.77
PhyloP100		-0.99
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: rs2278489; hg19: chr16-56926828;