rs17024708

Variant names:

• chr4-148419384-A-G
• rs17024708
• NM_000901.5:c.1757+15720T>C

Variant summary

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

The NM_000901.5(NR3C2):​c.1757+15720T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,150 control chromosomes in the GnomAD database, including 4,018 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 0.23 (4018 hom., cov: 32)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.553
• Publications: 1 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 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.1757+15720T>C		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.1757+15720T>C		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.1757+15720T>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.1757+15720T>C		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.1757+15720T>C		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.1757+15720T>C		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34423 AN: 152030 Hom.: 4017 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.214

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

GnomAD4 genome AF: 0.226 AC: 34442 AN: 152150 Hom.: 4018 Cov.: 32 AF XY: 0.227 AC XY: 16850 AN XY: 74382

African (AFR) AF: 0.242 AC: 10067 AN: 41516

American (AMR) AF: 0.165 AC: 2524 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3468

East Asian (EAS) AF: 0.140 AC: 725 AN: 5180

South Asian (SAS) AF: 0.145 AC: 699 AN: 4824

European-Finnish (FIN) AF: 0.317 AC: 3357 AN: 10574

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15646 AN: 67982

Other (OTH) AF: 0.212 AC: 447 AN: 2110

Alfa AF: 0.223 Hom.: 14990

Bravo AF: 0.217

Asia WGS AF: 0.150 AC: 519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.52
DANN	Benign	0.28
PhyloP100		-0.55
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: rs17024708; hg19: chr4-149340536;