16-56865272-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_001126108.2(SLC12A3):c.37G>C(p.Ala13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,613,802 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (2 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:2 O:1
• Conservation: PhyloP100: 0.512

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 134) in uniprot entity S12A3_HUMAN there are 22 pathogenic changes around while only 6 benign (79%) in NM_001126108.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.061490893).
• BP6: Variant 16-56865272-G-C is Benign according to our data. Variant chr16-56865272-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 562448.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.37G>C	p.Ala13Pro	missense_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.37G>C	p.Ala13Pro	missense_variant	1/26
SLC12A3	NM_001126107.2	c.37G>C	p.Ala13Pro	missense_variant	1/26
SLC12A3	NM_001410896.1	c.37G>C	p.Ala13Pro	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.37G>C	p.Ala13Pro	missense_variant	1/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.37G>C	p.Ala13Pro	missense_variant	1/26	1		A1
SLC12A3	ENST00000566786.5	c.37G>C	p.Ala13Pro	missense_variant	1/26	1		P4
SLC12A3	ENST00000262502.5	c.37G>C	p.Ala13Pro	missense_variant	1/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000651 AC: 163 AN: 250400 Hom.: 1 AF XY: 0.000701 AC XY: 95 AN XY: 135562

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000963 AC: 1408 AN: 1461470 Hom.: 2 Cov.: 32 AF XY: 0.000942 AC XY: 685 AN XY: 727052

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74492

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000661

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Uncertain:4 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 17, 2022	- -
Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 03-22-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2021	Reported in association with Gitelman syndrome in the published literature; however, additional clinical information and segregation information were not provided and it is unknown if a second variant was identified (Tseng MH et al., 2012); Reported along with a second variant in the SLC12A3 gene in a patient with Gitelman syndrome in the published literature; however, segregation information was not provided (Hureaux M et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 22679066, 21415153, 31672324, 28469853, 27535533) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	0.67
Dann	Benign	0.64
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.37	N;N;N;N
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.82	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.55
MVP		0.58
MPC		0.11
ClinPred		0.0032	T
GERP RS		1.7
Varity_R		0.092
gMVP		0.48

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: rs147200024; hg19: chr16-56899184;