16-56883033-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001126108.2(SLC12A3):c.1669+536C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 151,992 control chromosomes in the GnomAD database, including 37,676 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 0.70 (37676 hom., cov: 30)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.297

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1669+536C>T		intron_variant		ENST00000563236.6
SLC12A3	NM_000339.3	c.1669+536C>T		intron_variant
SLC12A3	NM_001126107.2	c.1666+536C>T		intron_variant
SLC12A3	NM_001410896.1	c.1666+536C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1669+536C>T		intron_variant		1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1669+536C>T		intron_variant		1		A1
SLC12A3	ENST00000566786.5	c.1666+536C>T		intron_variant		1		P4
SLC12A3	ENST00000262502.5	c.1666+536C>T		intron_variant		5		A1

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105742 AN: 151874 Hom.: 37634 Cov.: 30

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.714

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

GnomAD4 genome AF: 0.696 AC: 105844 AN: 151992 Hom.: 37676 Cov.: 30 AF XY: 0.699 AC XY: 51937 AN XY: 74276

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.690

Gnomad4 ASJ AF: 0.710

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.614

Gnomad4 OTH AF: 0.714

Alfa AF: 0.636 Hom.: 51599

Bravo AF: 0.703

Asia WGS AF: 0.687 AC: 2384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.8
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs8043560; hg19: chr16-56916945;