rs41511344

Positions:

• 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 ENST00000358102.8(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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR3C2 ENST00000358102.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• 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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a mutagenesis_site Alters receptor specificity. (size 0) in uniprot entity MCR_HUMAN
• 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 [Pathogenic]. Clinvar id is 8557.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.2429C>T	p.Ser810Leu	missense_variant	6/9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.2429C>T	p.Ser810Leu	missense_variant	6/9	1	NM_000901.5	ENSP00000350815	P4
	ENST00000514843.1	n.79+6001G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

NR3C2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

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

Pathogenic, flagged submission

literature only

OMIM

Jul 07, 2000

- -

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;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;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;