chr4-148182095-G-A

Variant names:

• chr4-148182095-G-A
• rs11099680
• NM_000901.5:c.2014+12651C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000901.5(NR3C2):​c.2014+12651C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,184 control chromosomes in the GnomAD database, including 46,628 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (46628 hom., cov: 33)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 3 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:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.2014+12651C>T		intron_variant	Intron 4 of 8	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.2014+12651C>T		intron_variant	Intron 4 of 8	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118154 AN: 152066 Hom.: 46573 Cov.: 33

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.732

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.762

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.777 AC: 118271 AN: 152184 Hom.: 46628 Cov.: 33 AF XY: 0.774 AC XY: 57558 AN XY: 74382

African (AFR) AF: 0.924 AC: 38424 AN: 41568

American (AMR) AF: 0.726 AC: 11093 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2732 AN: 3470

East Asian (EAS) AF: 0.732 AC: 3780 AN: 5162

South Asian (SAS) AF: 0.704 AC: 3392 AN: 4818

European-Finnish (FIN) AF: 0.705 AC: 7458 AN: 10574

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48836 AN: 67990

Other (OTH) AF: 0.765 AC: 1616 AN: 2112

Alfa AF: 0.753 Hom.: 5402

Bravo AF: 0.786

Asia WGS AF: 0.746 AC: 2595 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.77
PhyloP100		-1.2
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: rs11099680; hg19: chr4-149103246;