4-148182303-C-T

Variant names:

• chr4-148182303-C-T
• rs11099681
• NM_000901.5:c.2014+12443G>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.2014+12443G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,094 control chromosomes in the GnomAD database, including 46,601 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 (46601 hom., cov: 32)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.425
• Publications: 6 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

ENSG00000250354 (HGNC:58891):

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 = 0.917 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.2014+12443G>A		intron	N/A	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.2026+12443G>A		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.2014+12443G>A		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.2014+12443G>A		intron	N/A	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.2014+12443G>A		intron	N/A	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.2026+12443G>A		intron	N/A	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118108 AN: 151976 Hom.: 46546 Cov.: 32

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.733

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.762

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

GnomAD4 genome AF: 0.777 AC: 118224 AN: 152094 Hom.: 46601 Cov.: 32 AF XY: 0.774 AC XY: 57533 AN XY: 74330

African (AFR) AF: 0.924 AC: 38393 AN: 41530

American (AMR) AF: 0.726 AC: 11096 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2727 AN: 3464

East Asian (EAS) AF: 0.733 AC: 3789 AN: 5168

South Asian (SAS) AF: 0.704 AC: 3391 AN: 4816

European-Finnish (FIN) AF: 0.707 AC: 7455 AN: 10548

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48821 AN: 67978

Other (OTH) AF: 0.765 AC: 1613 AN: 2108

Alfa AF: 0.740 Hom.: 119377

Bravo AF: 0.786

Asia WGS AF: 0.745 AC: 2587 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.7
DANN	Benign	0.74
PhyloP100		0.42
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: rs11099681; hg19: chr4-149103454;