4-148152404-C-T

Variant names:

• chr4-148152404-C-T
• rs2272089
• NM_000901.5:c.2510+65G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000901.5(NR3C2):​c.2510+65G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,543,868 control chromosomes in the GnomAD database, including 413,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41612 hom., cov: 33)
  • Exomes 𝑓: 0.73 (371974 hom.)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00400
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-148152404-C-T is Benign according to our data. Variant chr4-148152404-C-T is described in ClinVar as Benign. ClinVar VariationId is 1270506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.769 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.2510+65G>A		intron	N/A	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.2522+65G>A		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.2510+65G>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.2510+65G>A		intron	N/A	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.2159+65G>A		intron	N/A	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.2522+65G>A		intron	N/A	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112411 AN: 151990 Hom.: 41570 Cov.: 33

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.721

GnomAD4 exome AF: 0.730 AC: 1016354 AN: 1391760 Hom.: 371974 Cov.: 20 AF XY: 0.728 AC XY: 506930 AN XY: 695898

African (AFR) AF: 0.779 AC: 24953 AN: 32028

American (AMR) AF: 0.689 AC: 30399 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 20001 AN: 25548

East Asian (EAS) AF: 0.769 AC: 30160 AN: 39224

South Asian (SAS) AF: 0.680 AC: 56983 AN: 83774

European-Finnish (FIN) AF: 0.719 AC: 38187 AN: 53096

Middle Eastern (MID) AF: 0.740 AC: 3121 AN: 4220

European-Non Finnish (NFE) AF: 0.732 AC: 770174 AN: 1051878

Other (OTH) AF: 0.732 AC: 42376 AN: 57864

GnomAD4 genome AF: 0.740 AC: 112508 AN: 152108 Hom.: 41612 Cov.: 33 AF XY: 0.736 AC XY: 54706 AN XY: 74348

African (AFR) AF: 0.776 AC: 32185 AN: 41484

American (AMR) AF: 0.702 AC: 10729 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 2705 AN: 3470

East Asian (EAS) AF: 0.757 AC: 3918 AN: 5174

South Asian (SAS) AF: 0.667 AC: 3210 AN: 4816

European-Finnish (FIN) AF: 0.710 AC: 7505 AN: 10566

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49819 AN: 67996

Other (OTH) AF: 0.723 AC: 1526 AN: 2112

Alfa AF: 0.732 Hom.: 68029

Bravo AF: 0.742

Asia WGS AF: 0.721 AC: 2511 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.57
DANN	Benign	0.51
PhyloP100		-0.0040
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: rs2272089; hg19: chr4-149073555;