chr4-148302131-A-T

Variant names:

• chr4-148302131-A-T
• rs11936376
• NM_000901.5:c.1758-42014T>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.1758-42014T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 152,074 control chromosomes in the GnomAD database, including 46,927 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 0.78 (46927 hom., cov: 31)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.704
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.1758-42014T>A		intron_variant	Intron 2 of 8	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.1758-42014T>A		intron_variant	Intron 2 of 8	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119121 AN: 151956 Hom.: 46885 Cov.: 31

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.779

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

GnomAD4 genome AF: 0.784 AC: 119223 AN: 152074 Hom.: 46927 Cov.: 31 AF XY: 0.782 AC XY: 58141 AN XY: 74330

African (AFR) AF: 0.787 AC: 32653 AN: 41496

American (AMR) AF: 0.792 AC: 12082 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 2833 AN: 3472

East Asian (EAS) AF: 0.843 AC: 4364 AN: 5178

South Asian (SAS) AF: 0.811 AC: 3905 AN: 4818

European-Finnish (FIN) AF: 0.706 AC: 7453 AN: 10564

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.783 AC: 53202 AN: 67982

Other (OTH) AF: 0.781 AC: 1643 AN: 2104

Alfa AF: 0.778 Hom.: 5740

Bravo AF: 0.791

Asia WGS AF: 0.823 AC: 2865 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.23
PhyloP100		-0.70
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: rs11936376; hg19: chr4-149223283;