rs41511344

Variant names:

• chr4-148152550-G-A
• rs41511344
• NM_000901.5:c.2429C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-148152550-G-A
• chr4-148152550-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3_Moderate

The NM_000901.5(NR3C2):​c.2429C>T​(p.Ser810Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). ClinVar reports functional evidence for this variant: "SCV005339150: Functional studies indicate this variant results in constitutive mineralocorticoid receptor activity by increasing the steroid-receptor complex (Geller et al. 2000. PubMed ID: 10884226" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR3C2 NM_000901.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 5.92
• Publications: 56 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

ENSG00000250354 (HGNC:58891):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005339150: Functional studies indicate this variant results in constitutive mineralocorticoid receptor activity by increasing the steroid-receptor complex (Geller et al. 2000. PubMed ID: 10884226; Pinon et al. 2004. PubMed ID: 15134816).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

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.2429C>T	p.Ser810Leu	missense	Exon 6 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.2441C>T	p.Ser814Leu	missense	Exon 6 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.2429C>T	p.Ser810Leu	missense	Exon 6 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.2429C>T	p.Ser810Leu	missense	Exon 6 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.2078C>T	p.Ser693Leu	missense	Exon 5 of 8	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000511528.1	TSL:5	c.2441C>T	p.Ser814Leu	missense	Exon 5 of 8	ENSP00000421481.1	P08235-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant pseudohypoaldosteronism type 1;C1854631:Pseudohyperaldosteronism type 2 (1)
1	-	-	Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy (1)
1	-	-	NR3C2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
PhyloP100		5.9
Varity_R		0.59
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41511344; hg19: chr4-149073701; COSMIC: COSV60998533;