chr16-56871520-T-C

Variant names:

• chr16-56871520-T-C
• rs4329913
• NM_001126108.2:c.852+784T>C

Variant summary

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

The NM_000339.3(SLC12A3):​c.852+784T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 152,180 control chromosomes in the GnomAD database, including 55,099 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 0.85 (55099 hom., cov: 31)
• Consequence: SLC12A3 NM_000339.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0910
• Publications: 13 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000339.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.852+784T>C		intron	N/A	NP_001119580.2
	SLC12A3	NM_000339.3		c.852+784T>C		intron	N/A	NP_000330.3
	SLC12A3	NM_001126107.2		c.849+784T>C		intron	N/A	NP_001119579.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.852+784T>C		intron	N/A	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.852+784T>C		intron	N/A	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.849+784T>C		intron	N/A	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128741 AN: 152062 Hom.: 55035 Cov.: 31

Gnomad AFR AF: 0.957

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.837

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

GnomAD4 genome AF: 0.847 AC: 128864 AN: 152180 Hom.: 55099 Cov.: 31 AF XY: 0.852 AC XY: 63374 AN XY: 74398

African (AFR) AF: 0.957 AC: 39773 AN: 41542

American (AMR) AF: 0.875 AC: 13386 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2709 AN: 3468

East Asian (EAS) AF: 0.993 AC: 5135 AN: 5172

South Asian (SAS) AF: 0.903 AC: 4349 AN: 4816

European-Finnish (FIN) AF: 0.803 AC: 8499 AN: 10582

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.768 AC: 52188 AN: 67982

Other (OTH) AF: 0.840 AC: 1775 AN: 2114

Alfa AF: 0.799 Hom.: 91638

Bravo AF: 0.857

Asia WGS AF: 0.934 AC: 3248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.0
DANN	Benign	0.44
PhyloP100		0.091
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: rs4329913; hg19: chr16-56905432;