15-48207778-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000338.3(SLC12A1):c.59G>A(p.Arg20His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,612,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: SLC12A1 NM_000338.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.66

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058493495).
• BP6: Variant 15-48207778-G-A is Benign according to our data. Variant chr15-48207778-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 886274.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A1	NM_000338.3	c.59G>A	p.Arg20His	missense_variant	2/27	ENST00000380993.8
SLC12A1	NM_001184832.2	c.59G>A	p.Arg20His	missense_variant	2/27
SLC12A1	NM_001384136.1	c.59G>A	p.Arg20His	missense_variant	2/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A1	ENST00000380993.8	c.59G>A	p.Arg20His	missense_variant	2/27	5	NM_000338.3	A1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000637 AC: 159 AN: 249734 Hom.: 0 AF XY: 0.000652 AC XY: 88 AN XY: 134906

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00131 AC: 1906 AN: 1460384 Hom.: 0 Cov.: 31 AF XY: 0.00123 AC XY: 892 AN XY: 726294

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74436

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000793 Hom.: 1

Bravo AF: 0.000714

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000927

EpiControl AF: 0.00137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 18, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 20 of the SLC12A1 protein (p.Arg20His). This variant is present in population databases (rs34661166, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 886274). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Bartter disease type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.058	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.1	M;.;M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
Polyphen		1.0	.;.;D;D;D;.;D;.
Vest4		0.54, 0.45, 0.44, 0.59, 0.76
MVP		0.97
MPC		0.70
ClinPred		0.095	T
GERP RS		5.4
Varity_R		0.33
gMVP		0.47

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

Other links and lift over

dbSNP: rs34661166; hg19: chr15-48499975; COSMIC: COSV57712273; COSMIC: COSV57712273;