4-148436862-G-C

Position:

• chr4-148436862-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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: Splicing: ADA: 0.00003813
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.27

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]

ACMG classification

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
NR3C2	NM_000901.5	c.-2C>G		splice_region_variant	2/9	ENST00000358102.8	NP_000892.2
NR3C2	NM_000901.5	c.-2C>G		5_prime_UTR_variant	2/9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.-2C>G		splice_region_variant	2/9	1	NM_000901.5	ENSP00000350815.3
NR3C2	ENST00000358102.8	c.-2C>G		5_prime_UTR_variant	2/9	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67407 AN: 151864 Hom.: 16714 Cov.: 32

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

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

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

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

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2016	This 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 submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 28249922, 20855654, 20884124, 23315997, 12483305) -
Benign, criteria provided, single submitter	not provided	Breakthrough 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

Other links and lift over

dbSNP: rs2070951; hg19: chr4-149358014;