chr4-148216474-C-G

Variant names:

• chr4-148216474-C-G
• rs2883930
• NM_000901.5:c.1898-21612G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001437657.1(NR3C2):​c.1910-21612G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 151,774 control chromosomes in the GnomAD database, including 7,965 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 0.31 (7965 hom., cov: 31)
• Consequence: NR3C2 NM_001437657.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.124
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437657.1. 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.1898-21612G>C		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.1910-21612G>C		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.1898-21612G>C		intron	N/A	NP_001424583.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.1898-21612G>C		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.1898-21612G>C		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.1910-21612G>C		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46570 AN: 151656 Hom.: 7943 Cov.: 31

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.315

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

GnomAD4 genome AF: 0.307 AC: 46633 AN: 151774 Hom.: 7965 Cov.: 31 AF XY: 0.302 AC XY: 22372 AN XY: 74196

African (AFR) AF: 0.457 AC: 18886 AN: 41338

American (AMR) AF: 0.197 AC: 3002 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1223 AN: 3462

East Asian (EAS) AF: 0.158 AC: 814 AN: 5160

South Asian (SAS) AF: 0.179 AC: 860 AN: 4808

European-Finnish (FIN) AF: 0.249 AC: 2621 AN: 10512

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18141 AN: 67934

Other (OTH) AF: 0.320 AC: 675 AN: 2110

Alfa AF: 0.170 Hom.: 346

Bravo AF: 0.314

Asia WGS AF: 0.210 AC: 729 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.54
DANN	Benign	0.39
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2883930; hg19: chr4-149137625;