chr16-56868317-T-G

Position:

chr16-56868317-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001126108.2(SLC12A3):c.450T>G(p.Ile150Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.132

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 linkuse as main transcript	c.450T>G	p.Ile150Met	missense_variant	3/26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 linkuse as main transcript	c.450T>G	p.Ile150Met	missense_variant	3/26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 linkuse as main transcript	c.447T>G	p.Ile149Met	missense_variant	3/26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 linkuse as main transcript	c.447T>G	p.Ile149Met	missense_variant	3/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.450T>G	p.Ile150Met	missense_variant	3/26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.450T>G	p.Ile150Met	missense_variant	3/26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.447T>G	p.Ile149Met	missense_variant	3/26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.447T>G	p.Ile149Met	missense_variant	3/26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727130

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:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 27, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 21, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

.;.;D;D

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.1

.;M;M;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.97

MutPred

0.69

.;Gain of MoRF binding (P = 0.0943);Gain of MoRF binding (P = 0.0943);.;

MVP

0.94

MPC

0.46

ClinPred

0.98

GERP RS

0.64

Varity_R

0.82

gMVP

0.93

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