15-48207769-A-G

Position:

chr15-48207769-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000338.3(SLC12A1):c.50A>G(p.Asn17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,611,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

SLC12A1
NM_000338.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.459

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018715799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A1	NM_000338.3 link	c.50A>G	p.Asn17Ser	missense_variant	2/27	ENST00000380993.8	NP_000329.2	Q13621-1Q8IUN5
SLC12A1	NM_001184832.2 link	c.50A>G	p.Asn17Ser	missense_variant	2/27		NP_001171761.1	Q13621-3B4DPF4
SLC12A1	NM_001384136.1 link	c.50A>G	p.Asn17Ser	missense_variant	2/27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8 link	c.50A>G	p.Asn17Ser	missense_variant	2/27	5	NM_000338.3	ENSP00000370381.3		Q13621-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000803

AC:

AN:

249064

Hom.:

AF XY:

0.0000595

AC XY:

AN XY:

134488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000438

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000795

AC:

116

AN:

1459444

Hom.:

Cov.:

AF XY:

0.0000772

AC XY:

AN XY:

725702

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000891

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SLC12A1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2023

The SLC12A1 c.50A>G variant is predicted to result in the amino acid substitution p.Asn17Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-48499966-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.50A>G (p.N17S) alteration is located in exon 2 (coding exon 1) of the SLC12A1 gene. This alteration results from a A to G substitution at nucleotide position 50, causing the asparagine (N) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bartter disease type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 07, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 17 of the SLC12A1 protein (p.Asn17Ser). This variant is present in population databases (rs757876818, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with SLC12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2387586). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.1

DANN

Benign

0.85

DEOGEN2

Benign

0.033

.;.;T;T;T;.;.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.80

.;T;.;.;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.019

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.67

N;.;N;N;N;N;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

0.49

.;.;.;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.77

.;.;.;T;T;T;T;T

Sift4G

Benign

0.89

.;.;.;T;T;T;T;T

Polyphen

0.0

.;.;B;B;B;.;B;.

Vest4

0.074, 0.078, 0.056, 0.045

MutPred

0.10

Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);Gain of phosphorylation at N17 (P = 0.1009);

MVP

0.68

MPC

0.11

ClinPred

0.030

GERP RS

2.9

Varity_R

0.026

gMVP

0.18

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