16-56902360-T-C

Position:

chr16-56902360-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.2721-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,760 control chromosomes in the GnomAD database, including 15,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2850 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13108 hom. )

Consequence

SLC12A3
NM_001126108.2 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.477

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-56902360-T-C is Benign according to our data. Variant chr16-56902360-T-C is described in ClinVar as [Benign]. Clinvar id is 255889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56902360-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
SLC12A3	NM_001126108.2 linkuse as main transcript	c.2721-13T>C	splice_polypyrimidine_tract_variant, intron_variant	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 linkuse as main transcript	c.2748-13T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_000330.3
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2745-13T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_001119579.2
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2718-13T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.2721-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001126108.2	ENSP00000456149	A1	P55017-1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26554

AN:

152006

Hom.:

2844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.299

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.0393

Gnomad SAS

AF:

0.0996

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.166

GnomAD3 exomes

AF:

0.131

AC:

33002

AN:

251386

Hom.:

2597

AF XY:

0.130

AC XY:

17617

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.0742

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.0353

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.128

AC:

187541

AN:

1461636

Hom.:

13108

Cov.:

AF XY:

0.128

AC XY:

92728

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.0775

Gnomad4 ASJ exome

AF:

0.152

Gnomad4 EAS exome

AF:

0.0232

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.148

Gnomad4 NFE exome

AF:

0.128

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.175

AC:

26584

AN:

152124

Hom.:

2850

Cov.:

AF XY:

0.173

AC XY:

12829

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.298

Gnomad4 AMR

AF:

0.118

Gnomad4 ASJ

AF:

0.155

Gnomad4 EAS

AF:

0.0390

Gnomad4 SAS

AF:

0.100

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.168

Alfa

AF:

0.175

Hom.:

510

Bravo

AF:

0.177

Asia WGS

AF:

0.127

AC:

440

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial hypokalemia-hypomagnesemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.7

DANN

Benign

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over