rs1552311

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 16/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V958G) has been classified as Uncertain significance.

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:10

Conservation

PhyloP100: 0.777

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 285) in uniprot entity S12A1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000338.3

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 [Likely_benign]. Clinvar id is 255874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48288516-T-C is described in Lovd as [Benign].

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/exons	MANE
SLC12A1	NM_000338.3 linkuse as main transcript	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27	ENST00000380993.8
SLC12A1	NM_001184832.2 linkuse as main transcript	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27
SLC12A1	NM_001384136.1 linkuse as main transcript	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A1	ENST00000380993.8 linkuse as main transcript	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27	5	NM_000338.3	A1	Q13621-1

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

GnomAD3 exomes

AF:

0.999

AC:

160933

AN:

161024

Hom.:

80422

AF XY:

1.00

AC XY:

84015

AN XY:

84050

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 SAS 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

Gnomad4 AFR exome

AF:

0.991

Gnomad4 AMR exome

AF:

0.999

Gnomad4 ASJ exome

AF:

1.00

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.999

GnomAD4 genome

AF:

0.998

AC:

151934

AN:

152314

Hom.:

75778

Cov.:

AF XY:

0.998

AC XY:

74287

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.991

Gnomad4 AMR

AF:

0.999

Gnomad4 ASJ

AF:

1.00

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.996

Alfa

AF:

0.999

Hom.:

112512

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2016	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. -

Bartter disease type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Dann

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.089

MetaRNN

Benign

5.7e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.0

N;.;N;N;N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.33

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

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

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