rs5525

Variant names:

• chr4-148435364-A-G
• rs5525
• NM_000901.5:c.1497T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-148435364-A-G
• chr4-148435364-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000901.5(NR3C2):​c.1497T>C​(p.Asp499Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,614,036 control chromosomes in the GnomAD database, including 631,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60353 hom., cov: 32)
  • Exomes 𝑓: 0.88 (571222 hom.)
• Consequence: NR3C2 NM_000901.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.787
• Publications: 35 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-148435364-A-G is Benign according to our data. Variant chr4-148435364-A-G is described in ClinVar as Benign. ClinVar VariationId is 256828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.787 with no splicing effect.
• 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.1497T>C	p.Asp499Asp	synonymous	Exon 2 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.1497T>C	p.Asp499Asp	synonymous	Exon 2 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.1497T>C	p.Asp499Asp	synonymous	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.1497T>C	p.Asp499Asp	synonymous	Exon 2 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.1497T>C	p.Asp499Asp	synonymous	Exon 2 of 8	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.1497T>C	p.Asp499Asp	synonymous	Exon 1 of 8	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135302 AN: 152054 Hom.: 60295 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.939

Gnomad NFE AF: 0.891

Gnomad OTH AF: 0.891

GnomAD2 exomes AF: 0.877 AC: 220532 AN: 251386 AF XY: 0.881

Gnomad AFR exome AF: 0.908

Gnomad AMR exome AF: 0.775

Gnomad ASJ exome AF: 0.903

Gnomad EAS exome AF: 0.862

Gnomad FIN exome AF: 0.914

Gnomad NFE exome AF: 0.891

Gnomad OTH exome AF: 0.876

GnomAD4 exome AF: 0.884 AC: 1291708 AN: 1461864 Hom.: 571222 Cov.: 84 AF XY: 0.885 AC XY: 643531 AN XY: 727232

African (AFR) AF: 0.903 AC: 30230 AN: 33480

American (AMR) AF: 0.786 AC: 35156 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 23539 AN: 26136

East Asian (EAS) AF: 0.835 AC: 33145 AN: 39700

South Asian (SAS) AF: 0.900 AC: 77641 AN: 86258

European-Finnish (FIN) AF: 0.913 AC: 48756 AN: 53412

Middle Eastern (MID) AF: 0.924 AC: 5329 AN: 5768

European-Non Finnish (NFE) AF: 0.885 AC: 984013 AN: 1111992

Other (OTH) AF: 0.892 AC: 53899 AN: 60394

GnomAD4 genome AF: 0.890 AC: 135414 AN: 152172 Hom.: 60353 Cov.: 32 AF XY: 0.890 AC XY: 66200 AN XY: 74398

African (AFR) AF: 0.907 AC: 37652 AN: 41514

American (AMR) AF: 0.834 AC: 12756 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3124 AN: 3472

East Asian (EAS) AF: 0.856 AC: 4421 AN: 5162

South Asian (SAS) AF: 0.906 AC: 4367 AN: 4822

European-Finnish (FIN) AF: 0.915 AC: 9689 AN: 10590

Middle Eastern (MID) AF: 0.935 AC: 273 AN: 292

European-Non Finnish (NFE) AF: 0.891 AC: 60590 AN: 68006

Other (OTH) AF: 0.893 AC: 1884 AN: 2110

Alfa AF: 0.840 Hom.: 115014

Bravo AF: 0.881

Asia WGS AF: 0.897 AC: 3120 AN: 3478

EpiCase AF: 0.895

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
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		0.79
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: rs5525; hg19: chr4-149356516; COSMIC: COSV108163664;