chr15-48247390-T-C

Variant names:

• chr15-48247390-T-C
• rs6493311
• NM_000338.3:c.1614T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.214
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• Bartter disease type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• antenatal Bartter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.1614T>C	p.Tyr538Tyr	synonymous_variant	Exon 13 of 27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.1614T>C	p.Tyr538Tyr	synonymous_variant	Exon 13 of 27		NP_001171761.1
SLC12A1	NM_001384136.1	c.1614T>C	p.Tyr538Tyr	synonymous_variant	Exon 13 of 27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.1614T>C	p.Tyr538Tyr	synonymous_variant	Exon 13 of 27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56695 AN: 151942 Hom.: 15063 Cov.: 33

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

GnomAD2 exomes AF: 0.289 AC: 72429 AN: 250762 AF XY: 0.277

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 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.: 30 AF XY: 0.229 AC XY: 166170 AN XY: 725906

African (AFR) AF: 0.762 AC: 25436 AN: 33380

American (AMR) AF: 0.288 AC: 12875 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6068 AN: 26106

East Asian (EAS) AF: 0.608 AC: 24124 AN: 39650

South Asian (SAS) AF: 0.295 AC: 25423 AN: 86084

European-Finnish (FIN) AF: 0.224 AC: 11954 AN: 53374

Middle Eastern (MID) AF: 0.264 AC: 1520 AN: 5760

European-Non Finnish (NFE) AF: 0.190 AC: 210512 AN: 1109754

Other (OTH) AF: 0.264 AC: 15892 AN: 60268

GnomAD4 genome AF: 0.374 AC: 56808 AN: 152060 Hom.: 15113 Cov.: 33 AF XY: 0.371 AC XY: 27573 AN XY: 74320

African (AFR) AF: 0.741 AC: 30741 AN: 41472

American (AMR) AF: 0.288 AC: 4401 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 810 AN: 3470

East Asian (EAS) AF: 0.578 AC: 2980 AN: 5156

South Asian (SAS) AF: 0.329 AC: 1583 AN: 4816

European-Finnish (FIN) AF: 0.209 AC: 2208 AN: 10562

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13242 AN: 67980

Other (OTH) AF: 0.339 AC: 717 AN: 2112

Alfa AF: 0.258 Hom.: 23722

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

Submissions by phenotype

not specified Benign:5

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Bartter disease type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.21
Mutation Taster		=99/1	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: rs6493311; hg19: chr15-48539587; COSMIC: COSV66795409;