NM_000901.5:c.*2471G>A

Variant names:

• chr4-148078873-C-T
• rs2871
• NM_000901.5:c.*2471G>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.*2471G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 152,572 control chromosomes in the GnomAD database, including 35,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35101 hom., cov: 34)
  • Exomes 𝑓: 0.63 (82 hom.)
• Consequence: NR3C2 NM_000901.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.568
• Publications: 11 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: Illumina, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pseudohyperaldosteronism type 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-148078873-C-T is Benign according to our data. Variant chr4-148078873-C-T is described in ClinVar as Benign. ClinVar VariationId is 347673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 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.*2471G>A		3_prime_UTR	Exon 9 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.*2471G>A		3_prime_UTR	Exon 9 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.*2471G>A		3_prime_UTR	Exon 9 of 9	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.*2471G>A		3_prime_UTR	Exon 9 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000625323.2	TSL:5	c.*2471G>A		3_prime_UTR	Exon 9 of 9	ENSP00000486719.1	P08235-3
	NR3C2	ENST00000344721.8	TSL:5	c.*2471G>A		3_prime_UTR	Exon 9 of 9	ENSP00000341390.4	P08235-1

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102962 AN: 152022 Hom.: 35056 Cov.: 34

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.632 AC: 273 AN: 432 Hom.: 82 Cov.: 0 AF XY: 0.662 AC XY: 172 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.631 AC: 269 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.677 AC: 103065 AN: 152140 Hom.: 35101 Cov.: 34 AF XY: 0.678 AC XY: 50403 AN XY: 74368

African (AFR) AF: 0.610 AC: 25294 AN: 41494

American (AMR) AF: 0.761 AC: 11636 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2412 AN: 3470

East Asian (EAS) AF: 0.827 AC: 4288 AN: 5182

South Asian (SAS) AF: 0.762 AC: 3666 AN: 4814

European-Finnish (FIN) AF: 0.625 AC: 6600 AN: 10562

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46944 AN: 68010

Other (OTH) AF: 0.687 AC: 1449 AN: 2108

Alfa AF: 0.693 Hom.: 129812

Bravo AF: 0.683

Asia WGS AF: 0.792 AC: 2749 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.7
DANN	Benign	0.76
PhyloP100		0.57
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: rs2871; hg19: chr4-149000024;