rs648912

Positions:

• chr3-15043362-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291694.2(NR2C2):​c.*354A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 156,624 control chromosomes in the GnomAD database, including 220 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 0.047 (197 hom., cov: 32)
  • Exomes 𝑓: 0.089 (23 hom.)
• Consequence: NR2C2 NM_001291694.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09

Genes affected

NR2C2 (HGNC:7972): (nuclear receptor subfamily 2 group C member 2) This gene encodes a protein that belongs to the nuclear hormone receptor family. Members of this family act as ligand-activated transcription factors and function in many biological processes such as development, cellular differentiation and homeostasis. The activated receptor/ligand complex is translocated to the nucleus where it binds to hormone response elements of target genes. The protein encoded by this gene plays a role in protecting cells from oxidative stress and damage induced by ionizing radiation. The lack of a similar gene in mouse results in growth retardation, severe spinal curvature, subfertility, premature aging, and prostatic intraepithelial neoplasia (PIN) development. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

MRPS25 (HGNC:14511): (mitochondrial ribosomal protein S25) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. A pseudogene corresponding to this gene is found on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2C2	NM_001291694.2	c.*354A>G		3_prime_UTR_variant	14/14	ENST00000425241.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2C2	ENST00000425241.6	c.*354A>G		3_prime_UTR_variant	14/14	2	NM_001291694.2	P1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7099 AN: 151872 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0548

GnomAD4 exome AF: 0.0893 AC: 414 AN: 4636 Hom.: 23 Cov.: 0 AF XY: 0.0955 AC XY: 236 AN XY: 2470

Gnomad4 AFR exome AF: 0.00476

Gnomad4 AMR exome AF: 0.0934

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0233

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.0911

Gnomad4 OTH exome AF: 0.0752

GnomAD4 genome AF: 0.0467 AC: 7095 AN: 151988 Hom.: 197 Cov.: 32 AF XY: 0.0491 AC XY: 3650 AN XY: 74270

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.0400

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.0218

Gnomad4 SAS AF: 0.0469

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0590

Gnomad4 OTH AF: 0.0542

Alfa AF: 0.0554 Hom.: 48

Bravo AF: 0.0407

Asia WGS AF: 0.0290 AC: 99 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.1
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs648912; hg19: chr3-15084869;