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. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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 (★).

• 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

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]

ENSG00000250354 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 27) in uniprot entity MCR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000901.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 4-148152550-G-A is Pathogenic according to our data. Variant chr4-148152550-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 8557.Status of the report is criteria_provided_single_submitter, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.2429C>T	p.Ser810Leu	missense_variant	Exon 6 of 9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.2429C>T	p.Ser810Leu	missense_variant	Exon 6 of 9	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

NR3C2-related disorder Pathogenic:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NR3C2 c.2429C>T variant is predicted to result in the amino acid substitution p.Ser810Leu. This variant was reported to segregate in a large family of individuals with early-onset hypertension; and in several female individuals, the condition was further exacerbated during pregnancy (Geller et al. 2000. PubMed ID: 10884226). 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). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy Pathogenic:1

Jul 07, 2000

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Autosomal dominant pseudohypoaldosteronism type 1;C1854631:Pseudohyperaldosteronism type 2 Uncertain:1

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.;D;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	-0.0050	N;.;N;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.52	N;.;N;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.34	T;.;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Vest4		0.84
MutPred		0.81		Loss of catalytic residue at S810 (P = 0.0248);.;Loss of catalytic residue at S810 (P = 0.0248);.;.;
MVP		0.95
MPC		1.9
ClinPred		0.69	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.96

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