chr4-148436862-G-C

Variant names:

• chr4-148436862-G-C
• rs2070951
• NM_000901.5:c.-2C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 96 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000901.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.-2C>G		splice_region	Exon 2 of 9	NP_000892.2
	NR3C2	NM_000901.5	MANE Select	c.-2C>G		5_prime_UTR	Exon 2 of 9	NP_000892.2
	NR3C2	NM_001437657.1		c.-2C>G		splice_region	Exon 2 of 9	NP_001424586.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.-2C>G		splice_region	Exon 2 of 9	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.-2C>G		splice_region	Exon 2 of 8	ENSP00000423510.1
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.-2C>G		5_prime_UTR	Exon 2 of 9	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

GnomAD2 exomes AF: 0.532 AC: 127947 AN: 240662 AF XY: 0.536

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 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

African (AFR) AF: 0.226 AC: 7527 AN: 33250

American (AMR) AF: 0.563 AC: 24810 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 10875 AN: 26024

East Asian (EAS) AF: 0.755 AC: 29934 AN: 39634

South Asian (SAS) AF: 0.614 AC: 52771 AN: 85924

European-Finnish (FIN) AF: 0.668 AC: 31412 AN: 47008

Middle Eastern (MID) AF: 0.384 AC: 2204 AN: 5738

European-Non Finnish (NFE) AF: 0.488 AC: 539869 AN: 1107268

Other (OTH) AF: 0.490 AC: 29452 AN: 60068

GnomAD4 genome AF: 0.444 AC: 67432 AN: 151982 Hom.: 16724 Cov.: 32 AF XY: 0.461 AC XY: 34210 AN XY: 74280

African (AFR) AF: 0.233 AC: 9638 AN: 41416

American (AMR) AF: 0.527 AC: 8053 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1390 AN: 3470

East Asian (EAS) AF: 0.764 AC: 3953 AN: 5172

South Asian (SAS) AF: 0.649 AC: 3120 AN: 4808

European-Finnish (FIN) AF: 0.679 AC: 7170 AN: 10554

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32799 AN: 67962

Other (OTH) AF: 0.425 AC: 899 AN: 2114

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 17, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autosomal dominant pseudohypoaldosteronism type 1 Benign:2

Mar 06, 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.

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28249922, 20855654, 20884124, 23315997, 12483305)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.58
PhyloP100		1.3
PromoterAI		-0.0022	Neutral
Mutation Taster		=288/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070951; hg19: chr4-149358014;