rs121912565

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000901.5(NR3C2):​c.2327A>G​(p.Gln776Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

NR3C2
NM_000901.5 missense

Scores

12
6
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.02
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a mutagenesis_site Reduces aldosterone binding and transcription transactivation. (size 0) in uniprot entity MCR_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 4-148154589-T-C is Pathogenic according to our data. Variant chr4-148154589-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 8563.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR3C2NM_000901.5 linkc.2327A>G p.Gln776Arg missense_variant Exon 5 of 9 ENST00000358102.8 NP_000892.2 P08235-1B0ZBF6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NR3C2ENST00000358102.8 linkc.2327A>G p.Gln776Arg missense_variant Exon 5 of 9 1 NM_000901.5 ENSP00000350815.3 P08235-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Pathogenic:1
Jun 01, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;.;D;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.87
.;D;D;.
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.7
M;.;M;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.6
D;.;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Vest4
0.94
MutPred
0.93
Gain of MoRF binding (P = 0.0479);.;Gain of MoRF binding (P = 0.0479);.;
MVP
0.99
MPC
1.7
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.96
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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.

Other links and lift over

dbSNP: rs121912565; hg19: chr4-149075740; API