chr4-148436323-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000901.5(NR3C2):​c.538G>T​(p.Val180Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V180I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR3C2 NM_000901.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321
• Publications: 159 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07917473).

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>T	p.Val180Phe	missense	Exon 2 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.538G>T	p.Val180Phe	missense	Exon 2 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.538G>T	p.Val180Phe	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>T	p.Val180Phe	missense	Exon 2 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.538G>T	p.Val180Phe	missense	Exon 2 of 8	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.538G>T	p.Val180Phe	missense	Exon 1 of 8	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 86

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 274087

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.22
DANN	Benign	0.91
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.68	T
PhyloP100		-0.32
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.029	D
Vest4		0.27
MutPred		0.29		Loss of ubiquitination at K182 (P = 0.0474)
MVP		0.15
MPC		0.18
ClinPred		0.11	T
GERP RS		-3.8
Varity_R		0.10
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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;