rs5522

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000358102.8(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. 14/20 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 ENST00000358102.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.538G>T	p.Val180Phe	missense_variant	2/9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.538G>T	p.Val180Phe	missense_variant	2/9	1	NM_000901.5	ENSP00000350815	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 86

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.079	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.53	N;.;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;.;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D
Vest4		0.27
MutPred		0.29		Loss of ubiquitination at K182 (P = 0.0474);Loss of ubiquitination at K182 (P = 0.0474);Loss of ubiquitination at K182 (P = 0.0474);Loss of ubiquitination at K182 (P = 0.0474);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs5522; hg19: chr4-149357475;