chr16-56897792-G-A

Variant names:

• chr16-56897792-G-A
• rs7187932
• NM_001126108.2:c.2634-1738G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001126108.2(SLC12A3):​c.2634-1738G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,016 control chromosomes in the GnomAD database, including 5,327 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 0.25 (5327 hom., cov: 32)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.276
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2634-1738G>A		intron_variant	Intron 22 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2661-1738G>A		intron_variant	Intron 22 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.2658-1738G>A		intron_variant	Intron 22 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.2631-1738G>A		intron_variant	Intron 22 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2634-1738G>A		intron_variant	Intron 22 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2661-1738G>A		intron_variant	Intron 22 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2658-1738G>A		intron_variant	Intron 22 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2631-1738G>A		intron_variant	Intron 22 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38163 AN: 151898 Hom.: 5318 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.251 AC: 38216 AN: 152016 Hom.: 5327 Cov.: 32 AF XY: 0.252 AC XY: 18690 AN XY: 74296

African (AFR) AF: 0.386 AC: 15983 AN: 41430

American (AMR) AF: 0.181 AC: 2775 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 869 AN: 3464

East Asian (EAS) AF: 0.282 AC: 1458 AN: 5168

South Asian (SAS) AF: 0.241 AC: 1159 AN: 4812

European-Finnish (FIN) AF: 0.227 AC: 2403 AN: 10574

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.189 AC: 12814 AN: 67966

Other (OTH) AF: 0.238 AC: 502 AN: 2108

Alfa AF: 0.212 Hom.: 11630

Bravo AF: 0.251

Asia WGS AF: 0.316 AC: 1098 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.70
PhyloP100		-0.28
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: rs7187932; hg19: chr16-56931704;