4-148114298-T-C

Variant names:

• chr4-148114298-T-C
• rs1879829
• NM_000901.5:c.2642-37A>G

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.2642-37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,609,708 control chromosomes in the GnomAD database, including 174,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16650 hom., cov: 33)
  • Exomes 𝑓: 0.46 (158118 hom.)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0110
• Publications: 11 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=-0.58).
• BP6: Variant 4-148114298-T-C is Benign according to our data. Variant chr4-148114298-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.2642-37A>G		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.2654-37A>G		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.2642-37A>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.2642-37A>G		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.2291-37A>G		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.2654-37A>G		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70524 AN: 151956 Hom.: 16640 Cov.: 33

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.448

GnomAD2 exomes AF: 0.486 AC: 119923 AN: 246940 AF XY: 0.482

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.677

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.463 AC: 675222 AN: 1457634 Hom.: 158118 Cov.: 33 AF XY: 0.462 AC XY: 334976 AN XY: 724628

African (AFR) AF: 0.454 AC: 15180 AN: 33426

American (AMR) AF: 0.500 AC: 22212 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 10324 AN: 26034

East Asian (EAS) AF: 0.664 AC: 26315 AN: 39616

South Asian (SAS) AF: 0.459 AC: 39347 AN: 85786

European-Finnish (FIN) AF: 0.551 AC: 29300 AN: 53168

Middle Eastern (MID) AF: 0.331 AC: 1910 AN: 5762

European-Non Finnish (NFE) AF: 0.454 AC: 503247 AN: 1109228

Other (OTH) AF: 0.455 AC: 27387 AN: 60208

GnomAD4 genome AF: 0.464 AC: 70567 AN: 152074 Hom.: 16650 Cov.: 33 AF XY: 0.465 AC XY: 34583 AN XY: 74330

African (AFR) AF: 0.456 AC: 18902 AN: 41484

American (AMR) AF: 0.464 AC: 7081 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1420 AN: 3470

East Asian (EAS) AF: 0.664 AC: 3433 AN: 5172

South Asian (SAS) AF: 0.464 AC: 2232 AN: 4808

European-Finnish (FIN) AF: 0.539 AC: 5697 AN: 10564

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.449 AC: 30513 AN: 67984

Other (OTH) AF: 0.452 AC: 954 AN: 2112

Alfa AF: 0.451 Hom.: 46813

Bravo AF: 0.458

Asia WGS AF: 0.540 AC: 1873 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

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: rs1879829; hg19: chr4-149035449; COSMIC: COSV60994022;