dbSNP rs121912574: NR3C2:p.Glu972Gly (chr4-148081384-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000901.5(NR3C2):c.2915A>G(p.Glu972Gly) variant causes a missense change. 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: 32)

Consequence

NR3C2
NM_000901.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.91

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant pseudohypoaldosteronism type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohyperaldosteronism type 2
Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

NR3C2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

PP5

Variant 4-148081384-T-C is Pathogenic according to our data. Variant chr4-148081384-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8572.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5 link	c.2915A>G	p.Glu972Gly	missense_variant	Exon 9 of 9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8 link	c.2915A>G	p.Glu972Gly	missense_variant	Exon 9 of 9	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1

Pathogenic:1

Nov 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;D;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.47

LIST_S2

Benign

0.0

.;D;D;D;.

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.69

N;.;N;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.0

D;.;D;D;D

Sift

Benign

0.055

T;.;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T

Vest4

0.73

ClinPred

0.97

GERP RS

5.9

Varity_R

0.50

gMVP

0.94

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over