rs5522

Variant names:

• chr4-148436323-C-T
• rs5522
• NM_000901.5:c.538G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-148436323-C-T
• chr4-148436323-C-A
• chr4-148436323-C-G

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.538G>A​(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,614,056 control chromosomes in the GnomAD database, including 630,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60280 hom., cov: 32)
  • Exomes 𝑓: 0.88 (570603 hom.)
• Consequence: NR3C2 NM_000901.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.321
• Publications: 161 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.438664E-7).
• BP6: Variant 4-148436323-C-T is Benign according to our data. Variant chr4-148436323-C-T is described in ClinVar as Benign. ClinVar VariationId is 256832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 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.538G>A	p.Val180Ile	missense	Exon 2 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.538G>A	p.Val180Ile	missense	Exon 2 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.538G>A	p.Val180Ile	missense	Exon 2 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.538G>A	p.Val180Ile	missense	Exon 2 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.538G>A	p.Val180Ile	missense	Exon 2 of 8	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.538G>A	p.Val180Ile	missense	Exon 1 of 8	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135239 AN: 152074 Hom.: 60223 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.914

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.890

Gnomad OTH AF: 0.891

GnomAD2 exomes AF: 0.877 AC: 220413 AN: 251426 AF XY: 0.881

Gnomad AFR exome AF: 0.907

Gnomad AMR exome AF: 0.775

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 0.862

Gnomad FIN exome AF: 0.914

Gnomad NFE exome AF: 0.891

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.883 AC: 1291015 AN: 1461862 Hom.: 570603 Cov.: 86 AF XY: 0.884 AC XY: 643200 AN XY: 727236

African (AFR) AF: 0.902 AC: 30213 AN: 33480

American (AMR) AF: 0.785 AC: 35119 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.892 AC: 23315 AN: 26134

East Asian (EAS) AF: 0.835 AC: 33160 AN: 39700

South Asian (SAS) AF: 0.900 AC: 77611 AN: 86258

European-Finnish (FIN) AF: 0.913 AC: 48750 AN: 53418

Middle Eastern (MID) AF: 0.924 AC: 5327 AN: 5768

European-Non Finnish (NFE) AF: 0.885 AC: 983685 AN: 1111990

Other (OTH) AF: 0.891 AC: 53835 AN: 60390

GnomAD4 genome AF: 0.889 AC: 135351 AN: 152194 Hom.: 60280 Cov.: 32 AF XY: 0.889 AC XY: 66180 AN XY: 74408

African (AFR) AF: 0.907 AC: 37663 AN: 41532

American (AMR) AF: 0.833 AC: 12745 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 3093 AN: 3470

East Asian (EAS) AF: 0.856 AC: 4431 AN: 5174

South Asian (SAS) AF: 0.905 AC: 4369 AN: 4826

European-Finnish (FIN) AF: 0.914 AC: 9690 AN: 10596

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.890 AC: 60543 AN: 67992

Other (OTH) AF: 0.892 AC: 1883 AN: 2110

Alfa AF: 0.886 Hom.: 274087

Bravo AF: 0.880

TwinsUK AF: 0.890 AC: 3300

ALSPAC AF: 0.889 AC: 3428

ESP6500AA AF: 0.912 AC: 4018

ESP6500EA AF: 0.890 AC: 7656

ExAC AF: 0.881 AC: 106982

Asia WGS AF: 0.896 AC: 3117 AN: 3478

EpiCase AF: 0.894

EpiControl AF: 0.898

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Autosomal dominant pseudohypoaldosteronism type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.019
DANN	Benign	0.42
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	7.4e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.32
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.45	T
Vest4		0.030
MPC		0.11
ClinPred		0.0065	T
GERP RS		-3.8
Varity_R		0.025
gMVP		0.090
Mutation Taster		=99/1	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: rs5522; hg19: chr4-149357475; COSMIC: COSV105905721;