rs144234574

Positions:

• chr4-148154738-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000901.5(NR3C2):​c.2178G>A​(p.Gln726=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,594,106 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (43 hom.)
• Consequence: NR3C2 NM_000901.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.43

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 4-148154738-C-T is Benign according to our data. Variant chr4-148154738-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.43 with no splicing effect.
• BS2: High AC in GnomAd4 at 659 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.2178G>A	p.Gln726=	synonymous_variant	5/9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.2178G>A	p.Gln726=	synonymous_variant	5/9	1	NM_000901.5	ENSP00000350815	P4
	ENST00000514843.1	n.79+8189C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 659 AN: 141368 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000955

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00497

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000890

Gnomad FIN AF: 0.00420

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00771

Gnomad OTH AF: 0.00361

GnomAD3 exomes AF: 0.00364 AC: 915 AN: 251276 Hom.: 3 AF XY: 0.00350 AC XY: 475 AN XY: 135824

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00611

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00602 AC: 8738 AN: 1452660 Hom.: 43 Cov.: 36 AF XY: 0.00583 AC XY: 4215 AN XY: 722518

Gnomad4 AFR exome AF: 0.000965

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00461

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.00724

Gnomad4 OTH exome AF: 0.00471

GnomAD4 genome AF: 0.00466 AC: 659 AN: 141446 Hom.: 2 Cov.: 31 AF XY: 0.00460 AC XY: 313 AN XY: 68026

Gnomad4 AFR AF: 0.000953

Gnomad4 AMR AF: 0.00348

Gnomad4 ASJ AF: 0.00497

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000893

Gnomad4 FIN AF: 0.00420

Gnomad4 NFE AF: 0.00771

Gnomad4 OTH AF: 0.00357

Alfa AF: 0.00588 Hom.: 1

Bravo AF: 0.00396

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NR3C2: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.5
DANN	Benign	0.77

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: rs144234574; hg19: chr4-149075889;