rs1552311

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_000338.3(SLC12A1):c.2873T>C(p.Val958Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,432,578 control chromosomes in the GnomAD database, including 715,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V958delinsA) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 1.0 ( 75778 hom., cov: 31)

Exomes 𝑓: 1.0 ( 639798 hom. )

Consequence

SLC12A1
NM_000338.3 missense, splice_region

Scores

Splicing: ADA: 0.00002561

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.777

Publications

27 publications found

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 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

SLC12A1 links:

ENSG00000309916 (HGNC:):

ENSG00000309916 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-48288516-TG-CGTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3577326.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=5.747869E-7).

BP6

Variant 15-48288516-T-C is Benign according to our data. Variant chr15-48288516-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC12A1	NM_000338.3 link	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	Exon 23 of 27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2 link	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	Exon 23 of 27		NP_001171761.1
SLC12A1	NM_001384136.1 link	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	Exon 23 of 27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8 link	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	Exon 23 of 27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes

AF:

0.998

AC:

151817

AN:

152196

Hom.:

75720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.991

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.999

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.996

GnomAD2 exomes

AF:

0.999

AC:

160933

AN:

161024

AF XY:

1.00

show subpopulations

Gnomad AFR exome

AF:

0.992

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

1.00

AC:

1279929

AN:

1280264

Hom.:

639798

Cov.:

AF XY:

1.00

AC XY:

637983

AN XY:

638128

show subpopulations

African (AFR)

AF:

0.991

AC:

28794

AN:

29062

American (AMR)

AF:

0.999

AC:

35222

AN:

35240

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

24374

AN:

24374

East Asian (EAS)

AF:

1.00

AC:

35432

AN:

35432

South Asian (SAS)

AF:

1.00

AC:

76117

AN:

76118

European-Finnish (FIN)

AF:

1.00

AC:

49400

AN:

49400

Middle Eastern (MID)

AF:

1.00

AC:

5450

AN:

5450

European-Non Finnish (NFE)

AF:

1.00

AC:

971067

AN:

971080

Other (OTH)

AF:

0.999

AC:

54073

AN:

54108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18382

36764

55146

73528

91910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.998

AC:

151934

AN:

152314

Hom.:

75778

Cov.:

AF XY:

0.998

AC XY:

74287

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.991

AC:

41218

AN:

41574

American (AMR)

AF:

0.999

AC:

15281

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5182

AN:

5182

South Asian (SAS)

AF:

1.00

AC:

4820

AN:

4820

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68033

AN:

68034

Other (OTH)

AF:

0.996

AC:

2106

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.999

Hom.:

175364

Bravo

AF:

0.997

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.992

AC:

4335

ESP6500EA

AF:

1.00

AC:

8510

ExAC

AF:

0.998

AC:

92168

Asia WGS

AF:

0.999

AC:

3474

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jun 04, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.2873T) is the minor allele. This a llele (T) has been identified in 0.62% (21/3400) of African chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs15523 11) and thus meets criteria to be classified as likely benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bartter disease type 1

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.13

.;.;T;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.12

.;T;.;.;T;T

MetaRNN

Benign

5.7e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.0

N;.;N;N;N;N

PhyloP100

0.78

PrimateAI

Benign

0.33

PROVEAN

Benign

1.8

.;.;.;N;N;N

REVEL

Benign

0.21

Sift

Benign

1.0

.;.;.;T;T;T

Sift4G

Benign

0.81

.;.;.;T;T;T

Polyphen

0.0

.;.;B;B;B;.

Vest4

0.026, 0.024

MPC

0.17

ClinPred

0.0083

GERP RS

4.5

Varity_R

0.023

gMVP

0.21

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.050

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over