4-148436862-G-C

Variant summary

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

The NM_000901.5(NR3C2):​c.-2C>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,600,986 control chromosomes in the GnomAD database, including 204,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16724 hom., cov: 32)
Exomes 𝑓: 0.50 ( 187766 hom. )

Consequence

NR3C2
NM_000901.5 splice_region

Scores

2
Splicing: ADA: 0.00003813
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.27
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 4-148436862-G-C is Benign according to our data. Variant chr4-148436862-G-C is described in ClinVar as [Benign]. Clinvar id is 256827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-148436862-G-C is described in Lovd as [Benign].
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/exons MANE Protein UniProt
NR3C2NM_000901.5 linkc.-2C>G splice_region_variant 2/9 ENST00000358102.8 NP_000892.2 P08235-1B0ZBF6
NR3C2NM_000901.5 linkc.-2C>G 5_prime_UTR_variant 2/9 ENST00000358102.8 NP_000892.2 P08235-1B0ZBF6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NR3C2ENST00000358102.8 linkc.-2C>G splice_region_variant 2/91 NM_000901.5 ENSP00000350815.3 P08235-1
NR3C2ENST00000358102.8 linkc.-2C>G 5_prime_UTR_variant 2/91 NM_000901.5 ENSP00000350815.3 P08235-1

Frequencies

GnomAD3 genomes
AF:
0.444
AC:
67407
AN:
151864
Hom.:
16714
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.233
Gnomad AMI
AF:
0.344
Gnomad AMR
AF:
0.527
Gnomad ASJ
AF:
0.401
Gnomad EAS
AF:
0.764
Gnomad SAS
AF:
0.648
Gnomad FIN
AF:
0.679
Gnomad MID
AF:
0.313
Gnomad NFE
AF:
0.483
Gnomad OTH
AF:
0.424
GnomAD3 exomes
AF:
0.532
AC:
127947
AN:
240662
Hom.:
35647
AF XY:
0.536
AC XY:
69982
AN XY:
130582
show subpopulations
Gnomad AFR exome
AF:
0.229
Gnomad AMR exome
AF:
0.568
Gnomad ASJ exome
AF:
0.419
Gnomad EAS exome
AF:
0.769
Gnomad SAS exome
AF:
0.622
Gnomad FIN exome
AF:
0.676
Gnomad NFE exome
AF:
0.489
Gnomad OTH exome
AF:
0.497
GnomAD4 exome
AF:
0.503
AC:
728854
AN:
1449004
Hom.:
187766
Cov.:
32
AF XY:
0.506
AC XY:
364917
AN XY:
721122
show subpopulations
Gnomad4 AFR exome
AF:
0.226
Gnomad4 AMR exome
AF:
0.563
Gnomad4 ASJ exome
AF:
0.418
Gnomad4 EAS exome
AF:
0.755
Gnomad4 SAS exome
AF:
0.614
Gnomad4 FIN exome
AF:
0.668
Gnomad4 NFE exome
AF:
0.488
Gnomad4 OTH exome
AF:
0.490
GnomAD4 genome
AF:
0.444
AC:
67432
AN:
151982
Hom.:
16724
Cov.:
32
AF XY:
0.461
AC XY:
34210
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.233
Gnomad4 AMR
AF:
0.527
Gnomad4 ASJ
AF:
0.401
Gnomad4 EAS
AF:
0.764
Gnomad4 SAS
AF:
0.649
Gnomad4 FIN
AF:
0.679
Gnomad4 NFE
AF:
0.483
Gnomad4 OTH
AF:
0.425
Alfa
AF:
0.484
Hom.:
12187
Bravo
AF:
0.418
Asia WGS
AF:
0.676
AC:
2350
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 17, 2016This is a RefSeq error. The reference base (c.-2C) is the minor allele. This all ele (C) has been identified in 48.2% (28400/58962) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 70951) and thus meets criteria to be classified as benign. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Autosomal dominant pseudohypoaldosteronism type 1 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2018This variant is associated with the following publications: (PMID: 28249922, 20855654, 20884124, 23315997, 12483305) -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
10
DANN
Benign
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000038
dbscSNV1_RF
Benign
0.086
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.

Other links and lift over

dbSNP: rs2070951; hg19: chr4-149358014; API