Variant rs2229209 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001126108.2(SLC12A3):c.1023C>G(p.Phe341Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F341F) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.64

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity S12A3_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001126108.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.1023C>G	p.Phe341Leu	missense_variant	8/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.1023C>G	p.Phe341Leu	missense_variant	8/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.1020C>G	p.Phe340Leu	missense_variant	8/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.1020C>G	p.Phe340Leu	missense_variant	8/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.1023C>G	p.Phe341Leu	missense_variant	8/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.1023C>G	p.Phe341Leu	missense_variant	8/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.1020C>G	p.Phe340Leu	missense_variant	8/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.1020C>G	p.Phe340Leu	missense_variant	8/26	5		A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

7.3

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

.;.;D;D

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

.;M;M;.

MutationTaster

Benign

9.2e-8

P;P;P;P

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.5

D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D

Polyphen

0.98

D;P;P;.

Vest4

0.72

MutPred

0.61

.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);.;

MVP

0.93

MPC

0.43

ClinPred

0.99

GERP RS

-4.8

Varity_R

0.63

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over