4-148081516-G-C

Variant names:

• chr4-148081516-G-C
• rs61763143
• NM_000901.5:c.2800-17C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000358102.8(NR3C2):​c.2800-17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,876 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (25 hom., cov: 32)
  • Exomes 𝑓: 0.016 (225 hom.)
• Consequence: NR3C2 ENST00000358102.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.375
• Publications: 0 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-148081516-G-C is Benign according to our data. Variant chr4-148081516-G-C is described in ClinVar as Benign. ClinVar VariationId is 256831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1827/152306) while in subpopulation NFE AF = 0.0193 (1311/68028). AF 95% confidence interval is 0.0184. There are 25 homozygotes in GnomAd4. There are 877 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1827 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358102.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.2800-17C>G		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.2812-17C>G		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.2800-17C>G		intron	N/A	NP_001424583.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.2800-17C>G		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.2449-17C>G		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.2812-17C>G		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1826 AN: 152188 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0123 AC: 3073 AN: 250434 AF XY: 0.0122

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0161 AC: 23557 AN: 1461570 Hom.: 225 Cov.: 31 AF XY: 0.0157 AC XY: 11441 AN XY: 727098

African (AFR) AF: 0.00197 AC: 66 AN: 33470

American (AMR) AF: 0.00490 AC: 219 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 67 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00186 AC: 160 AN: 86246

European-Finnish (FIN) AF: 0.0201 AC: 1074 AN: 53402

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5764

European-Non Finnish (NFE) AF: 0.0190 AC: 21143 AN: 1111774

Other (OTH) AF: 0.0130 AC: 787 AN: 60370

GnomAD4 genome AF: 0.0120 AC: 1827 AN: 152306 Hom.: 25 Cov.: 32 AF XY: 0.0118 AC XY: 877 AN XY: 74466

African (AFR) AF: 0.00320 AC: 133 AN: 41564

American (AMR) AF: 0.00725 AC: 111 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0202 AC: 215 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1311 AN: 68028

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.00628 Hom.: 1

Bravo AF: 0.0108

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		0.38
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: rs61763143; hg19: chr4-149002667;