rs11640954

Variant names:

• chr16-56874972-G-A
• rs11640954
• NM_001126108.2:c.1095+2186G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001126108.2(SLC12A3):​c.1095+2186G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,192 control chromosomes in the GnomAD database, including 2,757 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2757 hom., cov: 32)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69
• Publications: 9 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=-0.41).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1095+2186G>A		intron_variant	Intron 8 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1095+2186G>A		intron_variant	Intron 8 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.1092+2186G>A		intron_variant	Intron 8 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.1092+2186G>A		intron_variant	Intron 8 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1095+2186G>A		intron_variant	Intron 8 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1095+2186G>A		intron_variant	Intron 8 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1092+2186G>A		intron_variant	Intron 8 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1092+2186G>A		intron_variant	Intron 8 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28247 AN: 152072 Hom.: 2760 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.197

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.186 AC: 28257 AN: 152192 Hom.: 2757 Cov.: 32 AF XY: 0.186 AC XY: 13873 AN XY: 74388

African (AFR) AF: 0.163 AC: 6755 AN: 41516

American (AMR) AF: 0.225 AC: 3440 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 587 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1544 AN: 5178

South Asian (SAS) AF: 0.175 AC: 841 AN: 4818

European-Finnish (FIN) AF: 0.151 AC: 1603 AN: 10604

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12836 AN: 67998

Other (OTH) AF: 0.200 AC: 422 AN: 2112

Alfa AF: 0.185 Hom.: 531

Bravo AF: 0.194

Asia WGS AF: 0.217 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.92
PhyloP100		2.7
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: rs11640954; hg19: chr16-56908884;