rs11099694

Variant names:

• chr4-148346557-G-A
• rs11099694
• NM_000901.5:c.1758-86440C>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.1758-86440C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 151,802 control chromosomes in the GnomAD database, including 38,184 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 0.70 (38184 hom., cov: 30)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• Publications: 2 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.86 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.1758-86440C>T		intron	N/A	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.1758-86440C>T		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.1758-86440C>T		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.1758-86440C>T		intron	N/A	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.1758-86440C>T		intron	N/A	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.1758-86440C>T		intron	N/A	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106117 AN: 151682 Hom.: 38137 Cov.: 30

Gnomad AFR AF: 0.867

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.774

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.690

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

GnomAD4 genome AF: 0.700 AC: 106226 AN: 151802 Hom.: 38184 Cov.: 30 AF XY: 0.694 AC XY: 51465 AN XY: 74142

African (AFR) AF: 0.867 AC: 35950 AN: 41454

American (AMR) AF: 0.593 AC: 9010 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 2526 AN: 3472

East Asian (EAS) AF: 0.416 AC: 2133 AN: 5128

South Asian (SAS) AF: 0.616 AC: 2959 AN: 4806

European-Finnish (FIN) AF: 0.645 AC: 6809 AN: 10550

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44675 AN: 67882

Other (OTH) AF: 0.689 AC: 1452 AN: 2108

Alfa AF: 0.671 Hom.: 17560

Bravo AF: 0.701

Asia WGS AF: 0.542 AC: 1888 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.2
DANN	Benign	0.28
PhyloP100		0.34
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: rs11099694; hg19: chr4-149267709;