chr4-148163296-G-T

Variant names:

• chr4-148163296-G-T
• rs6816503
• NM_000901.5:c.2015-8395C>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.2015-8395C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,162 control chromosomes in the GnomAD database, including 3,213 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 0.17 (3213 hom., cov: 32)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 3 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: Orphanet, ClinGen, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohyperaldosteronism type 2

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

ENSG00000250354 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.2015-8395C>A		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.2027-8395C>A		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.2015-8395C>A		intron	N/A	NP_001424583.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.2015-8395C>A		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.2015-10683C>A		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.2027-8395C>A		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25377 AN: 152044 Hom.: 3198 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0770

Gnomad OTH AF: 0.132

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

GnomAD4 genome AF: 0.167 AC: 25427 AN: 152162 Hom.: 3213 Cov.: 32 AF XY: 0.168 AC XY: 12520 AN XY: 74394

African (AFR) AF: 0.355 AC: 14708 AN: 41460

American (AMR) AF: 0.102 AC: 1555 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 615 AN: 3472

East Asian (EAS) AF: 0.0821 AC: 425 AN: 5174

South Asian (SAS) AF: 0.180 AC: 869 AN: 4822

European-Finnish (FIN) AF: 0.160 AC: 1692 AN: 10604

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0770 AC: 5235 AN: 68010

Other (OTH) AF: 0.130 AC: 275 AN: 2112

Alfa AF: 0.130 Hom.: 322

Bravo AF: 0.169

Asia WGS AF: 0.138 AC: 483 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.4
DANN	Benign	0.83
PhyloP100		-0.26
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: rs6816503; hg19: chr4-149084447;