15-48247390-T-C

Position:

chr15-48247390-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000338.3(SLC12A1):c.1614T>C(p.Tyr538Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,611,078 control chromosomes in the GnomAD database, including 62,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 15113 hom., cov: 33)

Exomes 𝑓: 0.23 ( 47868 hom. )

Consequence

SLC12A1
NM_000338.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.214

Variant links:

Genes affected

SLC12A1 (HGNC:10910): (solute carrier family 12 member 1) This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

SLC12A1 links:

SLC12A1 (HGNC:):

SLC12A1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 15-48247390-T-C is Benign according to our data. Variant chr15-48247390-T-C is described in ClinVar as [Benign]. Clinvar id is 255872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48247390-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.214 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A1	NM_000338.3 linkuse as main transcript	c.1614T>C	p.Tyr538Tyr	synonymous_variant	13/27	ENST00000380993.8	NP_000329.2	Q13621-1Q8IUN5
SLC12A1	NM_001184832.2 linkuse as main transcript	c.1614T>C	p.Tyr538Tyr	synonymous_variant	13/27		NP_001171761.1	Q13621-3B4DPF4
SLC12A1	NM_001384136.1 linkuse as main transcript	c.1614T>C	p.Tyr538Tyr	synonymous_variant	13/27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8 linkuse as main transcript	c.1614T>C	p.Tyr538Tyr	synonymous_variant	13/27	5	NM_000338.3	ENSP00000370381.3		Q13621-1

Frequencies

GnomAD3 genomes

AF:

0.373

AC:

56695

AN:

151942

Hom.:

15063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.741

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.233

Gnomad EAS

AF:

0.578

Gnomad SAS

AF:

0.331

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.195

Gnomad OTH

AF:

0.333

GnomAD3 exomes

AF:

0.289

AC:

72429

AN:

250762

Hom.:

13734

AF XY:

0.277

AC XY:

37532

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.748

Gnomad AMR exome

AF:

0.285

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.564

Gnomad SAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.219

Gnomad NFE exome

AF:

0.195

Gnomad OTH exome

AF:

0.259

GnomAD4 exome

AF:

0.229

AC:

333804

AN:

1459018

Hom.:

47868

Cov.:

AF XY:

0.229

AC XY:

166170

AN XY:

725906

show subpopulations

Gnomad4 AFR exome

AF:

0.762

Gnomad4 AMR exome

AF:

0.288

Gnomad4 ASJ exome

AF:

0.232

Gnomad4 EAS exome

AF:

0.608

Gnomad4 SAS exome

AF:

0.295

Gnomad4 FIN exome

AF:

0.224

Gnomad4 NFE exome

AF:

0.190

Gnomad4 OTH exome

AF:

0.264

GnomAD4 genome

AF:

0.374

AC:

56808

AN:

152060

Hom.:

15113

Cov.:

AF XY:

0.371

AC XY:

27573

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.741

Gnomad4 AMR

AF:

0.288

Gnomad4 ASJ

AF:

0.233

Gnomad4 EAS

AF:

0.578

Gnomad4 SAS

AF:

0.329

Gnomad4 FIN

AF:

0.209

Gnomad4 NFE

AF:

0.195

Gnomad4 OTH

AF:

0.339

Alfa

AF:

0.230

Hom.:

11603

Bravo

AF:

0.394

Asia WGS

AF:

0.469

AC:

1629

AN:

3478

EpiCase

AF:

0.202

EpiControl

AF:

0.201

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Tyr538Tyr in exon 13 of SLC12A1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 83.66% (1106/1322 ) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6493311). -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bartter disease type 1

Benign:1

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

-0.59

CADD

Benign

0.65

DANN

Benign

0.71

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