16-56865271-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001126108.2(SLC12A3):c.36C>T(p.Asp12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,886 control chromosomes in the GnomAD database, including 3 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 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.44

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-56865271-C-T is Benign according to our data. Variant chr16-56865271-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319887.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr16-56865271-C-T is described in Lovd as [Benign]. Variant chr16-56865271-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.36C>T	p.Asp12=	synonymous_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.36C>T	p.Asp12=	synonymous_variant	1/26
SLC12A3	NM_001126107.2	c.36C>T	p.Asp12=	synonymous_variant	1/26
SLC12A3	NM_001410896.1	c.36C>T	p.Asp12=	synonymous_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.36C>T	p.Asp12=	synonymous_variant	1/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.36C>T	p.Asp12=	synonymous_variant	1/26	1		A1
SLC12A3	ENST00000566786.5	c.36C>T	p.Asp12=	synonymous_variant	1/26	1		P4
SLC12A3	ENST00000262502.5	c.36C>T	p.Asp12=	synonymous_variant	1/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000393

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: 0.00115

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000643 AC: 161 AN: 250400 Hom.: 0 AF XY: 0.000583 AC XY: 79 AN XY: 135578

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00106 AC: 1548 AN: 1461528 Hom.: 3 Cov.: 32 AF XY: 0.00101 AC XY: 735 AN XY: 727078

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74500

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000782

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	12
Dann	Benign	0.72

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: rs117987946; hg19: chr16-56899183;