rs144234574

Variant names:

• chr4-148154738-C-T
• rs144234574
• NM_000901.5:c.2178G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000901.5(NR3C2):​c.2178G>A​(p.Gln726Gln) 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
• Publications: 2 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: Orphanet, ClinGen, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohyperaldosteronism type 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000250354 (HGNC:58891):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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,Unknown gene.

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.2178G>A	p.Gln726Gln	synonymous	Exon 5 of 9	NP_000892.2
	NR3C2	NM_001437657.1		c.2190G>A	p.Gln730Gln	synonymous	Exon 5 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.2178G>A	p.Gln726Gln	synonymous	Exon 5 of 9	NP_001424583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.2178G>A	p.Gln726Gln	synonymous	Exon 5 of 9	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.2015-2125G>A		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.2190G>A	p.Gln730Gln	synonymous	Exon 4 of 8	ENSP00000421481.1

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

GnomAD2 exomes AF: 0.00364 AC: 915 AN: 251276 AF XY: 0.00350

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 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

African (AFR) AF: 0.000965 AC: 32 AN: 33166

American (AMR) AF: 0.00155 AC: 69 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 119 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.00133 AC: 115 AN: 86146

European-Finnish (FIN) AF: 0.00202 AC: 107 AN: 52856

Middle Eastern (MID) AF: 0.000877 AC: 5 AN: 5704

European-Non Finnish (NFE) AF: 0.00724 AC: 8010 AN: 1105702

Other (OTH) AF: 0.00471 AC: 281 AN: 59720

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

African (AFR) AF: 0.000953 AC: 36 AN: 37790

American (AMR) AF: 0.00348 AC: 44 AN: 12652

Ashkenazi Jewish (ASJ) AF: 0.00497 AC: 17 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 4640

South Asian (SAS) AF: 0.000893 AC: 4 AN: 4480

European-Finnish (FIN) AF: 0.00420 AC: 36 AN: 8564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.00771 AC: 515 AN: 66770

Other (OTH) AF: 0.00357 AC: 7 AN: 1960

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.5
DANN	Benign	0.77
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144234574; hg19: chr4-149075889;