16-56865253-AAC-A

Position:

chr16-56865253-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.20_21del(p.Thr7ArgfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.42

Variant links:

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]

SLC12A3 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 346 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56865253-AAC-A is Pathogenic according to our data. Variant chr16-56865253-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 817609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.20_21del	p.Thr7ArgfsTer22	frameshift_variant	1/26	5		A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249530

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135208

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:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461422

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2022	This variant is present in population databases (rs750710315, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Thr7Argfs*22) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This premature translational stop signal has been observed in individual(s) with Gitelman syndrome (PMID: 20675610, 21415153, 31672324). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817609). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17699451, 21415153, 35628451, 31672324, 20675610) -

Familial hypokalemia-hypomagnesemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 29, 2018

This patient is heterozygous for the two base deletion (c.20_21del) in exon 1 of SLC12A3 gene. This frameshifting variant is predicted to create a premature stop codon (p.Thr7Argfs*22) and may result in a null allele due to nonsense-mediated mRNA decay. To our knowledge, c.20_21del has not been previously reported to be a disease causing variant and it has not been reported in the ExAC allele frequency database (http://exac.broadinstitute.org). According to ACMG guidelines, this variant is considered to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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