15-48207807-C-G

Variant summary

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

The NM_000338.3(SLC12A1):c.88C>G(p.His30Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. H30H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLC12A1
NM_000338.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.41

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=0.044272095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A1	NM_000338.3 linkuse as main transcript	c.88C>G	p.His30Asp	missense_variant	2/27	ENST00000380993.8
SLC12A1	NM_001184832.2 linkuse as main transcript	c.88C>G	p.His30Asp	missense_variant	2/27
SLC12A1	NM_001384136.1 linkuse as main transcript	c.88C>G	p.His30Asp	missense_variant	2/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A1	ENST00000380993.8 linkuse as main transcript	c.88C>G	p.His30Asp	missense_variant	2/27	5	NM_000338.3	A1	Q13621-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250772

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000795

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

193

AN:

1461608

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.000165

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000992

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.88C>G (p.H30D) alteration is located in exon 2 (coding exon 1) of the SLC12A1 gene. This alteration results from a C to G substitution at nucleotide position 88, causing the histidine (H) at amino acid position 30 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 30 of the SLC12A1 protein (p.His30Asp). This variant is present in population databases (rs199719506, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SLC12A1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

0.089

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.14

Cadd

Benign

Dann

Benign

0.89

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.19

M_CAP

Benign

0.032

MetaRNN

Benign

0.044

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

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

L;.;L;L;L;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.31

Polyphen

0.0030, 0.020

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

Vest4

0.36, 0.29, 0.31, 0.34

MutPred

0.097

Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);Gain of phosphorylation at S32 (P = 0.1096);

MVP

0.82

MPC

0.20

ClinPred

0.057

GERP RS

5.4

Varity_R

0.091

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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