4-148308186-G-T

Variant names:

• chr4-148308186-G-T
• rs3846329
• NM_000901.5:c.1758-48069C>A

Variant summary

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

The NM_000901.5(NR3C2):​c.1758-48069C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 152,032 control chromosomes in the GnomAD database, including 3,200 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 0.20 (3200 hom., cov: 31)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370
• Publications: 7 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Ambry Genetics
• pseudohyperaldosteronism type 2

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.27 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.1758-48069C>A		intron	N/A	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.1758-48069C>A		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.1758-48069C>A		intron	N/A	NP_001424583.1	B0ZBF6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.1758-48069C>A		intron	N/A	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.1758-48069C>A		intron	N/A	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.1758-48069C>A		intron	N/A	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30406 AN: 151914 Hom.: 3196 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.200 AC: 30440 AN: 152032 Hom.: 3200 Cov.: 31 AF XY: 0.201 AC XY: 14928 AN XY: 74306

African (AFR) AF: 0.159 AC: 6586 AN: 41476

American (AMR) AF: 0.277 AC: 4233 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3472

East Asian (EAS) AF: 0.260 AC: 1342 AN: 5166

South Asian (SAS) AF: 0.198 AC: 956 AN: 4818

European-Finnish (FIN) AF: 0.172 AC: 1810 AN: 10550

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13918 AN: 67976

Other (OTH) AF: 0.209 AC: 440 AN: 2110

Alfa AF: 0.203 Hom.: 13708

Bravo AF: 0.207

Asia WGS AF: 0.248 AC: 860 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.48
PhyloP100		-0.037
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: rs3846329; hg19: chr4-149229338;