4-148441592-G-A

Variant names:

• chr4-148441592-G-A
• rs7658048
• NM_000901.5:c.-3+568C>T

Variant summary

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

The NM_000901.5(NR3C2):​c.-3+568C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,154 control chromosomes in the GnomAD database, including 6,578 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 0.27 (6578 hom., cov: 33)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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: 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=-0.51).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 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.-3+568C>T		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.-3+568C>T		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.-3+2934C>T		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.-3+568C>T		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.-3+568C>T		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000625323.2	TSL:5	c.-3+568C>T		intron	N/A	ENSP00000486719.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41713 AN: 152036 Hom.: 6574 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.0282

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.274 AC: 41743 AN: 152154 Hom.: 6578 Cov.: 33 AF XY: 0.263 AC XY: 19586 AN XY: 74380

African (AFR) AF: 0.174 AC: 7222 AN: 41518

American (AMR) AF: 0.227 AC: 3467 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3468

East Asian (EAS) AF: 0.0282 AC: 146 AN: 5174

South Asian (SAS) AF: 0.203 AC: 979 AN: 4826

European-Finnish (FIN) AF: 0.212 AC: 2240 AN: 10590

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 25037 AN: 67972

Other (OTH) AF: 0.308 AC: 650 AN: 2110

Alfa AF: 0.339 Hom.: 35679

Bravo AF: 0.272

Asia WGS AF: 0.117 AC: 411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		1.0
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: rs7658048; hg19: chr4-149362744;