4-148091580-T-C

Variant names:

• chr4-148091580-T-C
• rs6535579
• NM_000901.5:c.2800-10081A>G

Variant summary

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

The NM_000901.5(NR3C2):​c.2800-10081A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 152,170 control chromosomes in the GnomAD database, including 38,657 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 0.71 (38657 hom., cov: 33)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.2800-10081A>G		intron_variant	Intron 8 of 8	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.2800-10081A>G		intron_variant	Intron 8 of 8	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108330 AN: 152052 Hom.: 38599 Cov.: 33

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.710

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

GnomAD4 genome AF: 0.713 AC: 108453 AN: 152170 Hom.: 38657 Cov.: 33 AF XY: 0.714 AC XY: 53056 AN XY: 74360

African (AFR) AF: 0.699 AC: 29004 AN: 41502

American (AMR) AF: 0.777 AC: 11887 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2408 AN: 3470

East Asian (EAS) AF: 0.818 AC: 4233 AN: 5172

South Asian (SAS) AF: 0.747 AC: 3599 AN: 4818

European-Finnish (FIN) AF: 0.674 AC: 7134 AN: 10580

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47877 AN: 68002

Other (OTH) AF: 0.715 AC: 1513 AN: 2116

Alfa AF: 0.699 Hom.: 19662

Bravo AF: 0.720

Asia WGS AF: 0.792 AC: 2750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.69
DANN	Benign	0.32
PhyloP100		-1.3
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: rs6535579; hg19: chr4-149012731;