rs2070951

Variant names:

• chr4-148436862-G-C
• rs2070951
• NM_000901.5:c.-2C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-148436862-G-C
• chr4-148436862-G-A
• chr4-148436862-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000901.5(NR3C2):​c.-2C>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,600,986 control chromosomes in the GnomAD database, including 204,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16724 hom., cov: 32)
  • Exomes 𝑓: 0.50 (187766 hom.)
• Consequence: NR3C2 NM_000901.5 splice_region
• Scores: Splicing: ADA: 0.00003813
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.27
• Publications: 96 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-148436862-G-C is Benign according to our data. Variant chr4-148436862-G-C is described in ClinVar as Benign. ClinVar VariationId is 256827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

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.-2C>G		splice_region	Exon 2 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_000901.5	MANE Select	c.-2C>G		5_prime_UTR	Exon 2 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.-2C>G		splice_region	Exon 2 of 9	NP_001424586.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.-2C>G		splice_region	Exon 2 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.-2C>G		splice_region	Exon 2 of 8	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.-2C>G		5_prime_UTR	Exon 2 of 9	ENSP00000350815.3	P08235-1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67407 AN: 151864 Hom.: 16714 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.424

GnomAD2 exomes AF: 0.532 AC: 127947 AN: 240662 AF XY: 0.536

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.568

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.676

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.497

GnomAD4 exome AF: 0.503 AC: 728854 AN: 1449004 Hom.: 187766 Cov.: 32 AF XY: 0.506 AC XY: 364917 AN XY: 721122

African (AFR) AF: 0.226 AC: 7527 AN: 33250

American (AMR) AF: 0.563 AC: 24810 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 10875 AN: 26024

East Asian (EAS) AF: 0.755 AC: 29934 AN: 39634

South Asian (SAS) AF: 0.614 AC: 52771 AN: 85924

European-Finnish (FIN) AF: 0.668 AC: 31412 AN: 47008

Middle Eastern (MID) AF: 0.384 AC: 2204 AN: 5738

European-Non Finnish (NFE) AF: 0.488 AC: 539869 AN: 1107268

Other (OTH) AF: 0.490 AC: 29452 AN: 60068

GnomAD4 genome AF: 0.444 AC: 67432 AN: 151982 Hom.: 16724 Cov.: 32 AF XY: 0.461 AC XY: 34210 AN XY: 74280

African (AFR) AF: 0.233 AC: 9638 AN: 41416

American (AMR) AF: 0.527 AC: 8053 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1390 AN: 3470

East Asian (EAS) AF: 0.764 AC: 3953 AN: 5172

South Asian (SAS) AF: 0.649 AC: 3120 AN: 4808

European-Finnish (FIN) AF: 0.679 AC: 7170 AN: 10554

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32799 AN: 67962

Other (OTH) AF: 0.425 AC: 899 AN: 2114

Alfa AF: 0.484 Hom.: 12187

Bravo AF: 0.418

Asia WGS AF: 0.676 AC: 2350 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Autosomal dominant pseudohypoaldosteronism type 1 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.58
PhyloP100		1.3
PromoterAI		-0.0022	Neutral
Mutation Taster		=288/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.086
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: rs2070951; hg19: chr4-149358014;