NM_000901.5:c.2178G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000901.5(NR3C2):c.2178G>A(p.Gln726Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,594,106 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0060 ( 43 hom. )

Consequence

NR3C2
NM_000901.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.43

Publications

2 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:

ENSG00000250354 (HGNC:):

ENSG00000250354 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 4-148154738-C-T is Benign according to our data. Variant chr4-148154738-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.43 with no splicing effect.

BS2

High AC in GnomAd4 at 659 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5 link	c.2178G>A	p.Gln726Gln	synonymous_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
NR3C2	ENST00000358102.8 link	c.2178G>A	p.Gln726Gln	synonymous_variant	Exon 5 of 9	1	NM_000901.5	ENSP00000350815.3		P08235-1

Frequencies

GnomAD3 genomes

AF:

0.00466

AC:

659

AN:

141368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000955

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00348

Gnomad ASJ

AF:

0.00497

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000890

Gnomad FIN

AF:

0.00420

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00771

Gnomad OTH

AF:

0.00361

GnomAD2 exomes

AF:

0.00364

AC:

915

AN:

251276

AF XY:

0.00350

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00602

AC:

8738

AN:

1452660

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

4215

AN XY:

722518

show subpopulations

African (AFR)

AF:

0.000965

AC:

AN:

33166

American (AMR)

AF:

0.00155

AC:

AN:

44444

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

119

AN:

25796

East Asian (EAS)

AF:

0.00

AC:

AN:

39126

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86146

European-Finnish (FIN)

AF:

0.00202

AC:

107

AN:

52856

Middle Eastern (MID)

AF:

0.000877

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00724

AC:

8010

AN:

1105702

Other (OTH)

AF:

0.00471

AC:

281

AN:

59720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

529

1058

1586

2115

2644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00466

AC:

659

AN:

141446

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

313

AN XY:

68026

show subpopulations

African (AFR)

AF:

0.000953

AC:

AN:

37790

American (AMR)

AF:

0.00348

AC:

AN:

12652

Ashkenazi Jewish (ASJ)

AF:

0.00497

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

4640

South Asian (SAS)

AF:

0.000893

AC:

AN:

4480

European-Finnish (FIN)

AF:

0.00420

AC:

AN:

8564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.00771

AC:

515

AN:

66770

Other (OTH)

AF:

0.00357

AC:

AN:

1960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00588

Hom.:

Bravo

AF:

0.00396

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NR3C2: BP4, BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant pseudohypoaldosteronism type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.5

(source)

DANN

Benign

0.77

PhyloP100

3.4

Mutation Taster

=100/0

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over