chr4-148436323-C-T

Position:

chr4-148436323-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000358102.8(NR3C2):c.538G>A(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,614,056 control chromosomes in the GnomAD database, including 630,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 60280 hom., cov: 32)

Exomes 𝑓: 0.88 ( 570603 hom. )

Consequence

NR3C2
ENST00000358102.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.321

Variant links:

Genes affected

NR3C2 (HGNC:7979): (nuclear receptor subfamily 3 group C member 2) This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NR3C2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.438664E-7).

BP6

Variant 4-148436323-C-T is Benign according to our data. Variant chr4-148436323-C-T is described in ClinVar as [Benign]. Clinvar id is 256832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-148436323-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C2	NM_000901.5 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/9	1	NM_000901.5	ENSP00000350815	P4	P08235-1

Frequencies

GnomAD3 genomes

AF:

0.889

AC:

135239

AN:

152074

Hom.:

60223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.907

Gnomad AMI

AF:

0.726

Gnomad AMR

AF:

0.834

Gnomad ASJ

AF:

0.891

Gnomad EAS

AF:

0.857

Gnomad SAS

AF:

0.904

Gnomad FIN

AF:

0.914

Gnomad MID

AF:

0.940

Gnomad NFE

AF:

0.890

Gnomad OTH

AF:

0.891

GnomAD3 exomes

AF:

0.877

AC:

220413

AN:

251426

Hom.:

96836

AF XY:

0.881

AC XY:

119686

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.907

Gnomad AMR exome

AF:

0.775

Gnomad ASJ exome

AF:

0.894

Gnomad EAS exome

AF:

0.862

Gnomad SAS exome

AF:

0.900

Gnomad FIN exome

AF:

0.914

Gnomad NFE exome

AF:

0.891

Gnomad OTH exome

AF:

0.875

GnomAD4 exome

AF:

0.883

AC:

1291015

AN:

1461862

Hom.:

570603

Cov.:

AF XY:

0.884

AC XY:

643200

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.902

Gnomad4 AMR exome

AF:

0.785

Gnomad4 ASJ exome

AF:

0.892

Gnomad4 EAS exome

AF:

0.835

Gnomad4 SAS exome

AF:

0.900

Gnomad4 FIN exome

AF:

0.913

Gnomad4 NFE exome

AF:

0.885

Gnomad4 OTH exome

AF:

0.891

GnomAD4 genome

AF:

0.889

AC:

135351

AN:

152194

Hom.:

60280

Cov.:

AF XY:

0.889

AC XY:

66180

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.907

Gnomad4 AMR

AF:

0.833

Gnomad4 ASJ

AF:

0.891

Gnomad4 EAS

AF:

0.856

Gnomad4 SAS

AF:

0.905

Gnomad4 FIN

AF:

0.914

Gnomad4 NFE

AF:

0.890

Gnomad4 OTH

AF:

0.892

Alfa

AF:

0.886

Hom.:

146129

Bravo

AF:

0.880

TwinsUK

AF:

0.890

AC:

3300

ALSPAC

AF:

0.889

AC:

3428

ESP6500AA

AF:

0.912

AC:

4018

ESP6500EA

AF:

0.890

AC:

7656

ExAC

AF:

0.881

AC:

106982

Asia WGS

AF:

0.896

AC:

3117

AN:

3478

EpiCase

AF:

0.894

EpiControl

AF:

0.898

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Val180Ile in exon 2 of NR3C2: This variant is not expected to have clinical si gnificance because it has been identified in 91.35% (6042/6614) of Finnish chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs5522). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 28249922, 12483305, 18468809, 19955850, 22584804, 22407082) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal dominant pseudohypoaldosteronism type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.019

DANN

Benign

0.42

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.054

.;T;T;T;.

MetaRNN

Benign

7.4e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.050

N;.;N;N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;.;T;T;T

Sift4G

Benign

0.45

T;T;T;T;T

Vest4

0.030

MPC

0.11

ClinPred

0.0065

GERP RS

-3.8

Varity_R

0.025

gMVP

0.090

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