Genetic Variant NM_000901.5:c.-2-358C>G (chr4-148437220-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000901.5(NR3C2):c.-2-358C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 152,072 control chromosomes in the GnomAD database, including 16,430 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 16430 hom., cov: 33)

Consequence

NR3C2
NM_000901.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.38

Publications

13 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5 link	c.-2-358C>G		intron_variant	Intron 1 of 8	ENST00000358102.8	NP_000892.2	P08235-1B0ZBF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8 link	c.-2-358C>G		intron_variant	Intron 1 of 8	1	NM_000901.5	ENSP00000350815.3		P08235-1

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

66124

AN:

151954

Hom.:

16419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.764

Gnomad SAS

AF:

0.647

Gnomad FIN

AF:

0.680

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.482

Gnomad OTH

AF:

0.416

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.435

AC:

66150

AN:

152072

Hom.:

16430

Cov.:

AF XY:

0.451

AC XY:

33551

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.203

AC:

8419

AN:

41484

American (AMR)

AF:

0.524

AC:

8003

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1389

AN:

3468

East Asian (EAS)

AF:

0.764

AC:

3947

AN:

5168

South Asian (SAS)

AF:

0.648

AC:

3126

AN:

4824

European-Finnish (FIN)

AF:

0.680

AC:

7182

AN:

10566

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.482

AC:

32793

AN:

67970

Other (OTH)

AF:

0.417

AC:

882

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1734

3469

5203

6938

8672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.452

Hom.:

2079

Bravo

AF:

0.409

Asia WGS

AF:

0.675

AC:

2346

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.0

(source)

DANN

Benign

0.69

PhyloP100

1.4

PromoterAI

-0.0028

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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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NM_000901.5:c.-2-358C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over