rs2230444

Positions:

• chr3-15039189-G-A
• chr3-15039189-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001291694.2(NR2C2):​c.1578G>A​(p.Gln526=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0831 in 1,613,676 control chromosomes in the GnomAD database, including 6,219 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 0.072 (432 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5787 hom.)
• Consequence: NR2C2 NM_001291694.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2C2	NM_001291694.2	c.1578G>A	p.Gln526=	synonymous_variant	13/14	ENST00000425241.6	NP_001278623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2C2	ENST00000425241.6	c.1578G>A	p.Gln526=	synonymous_variant	13/14	2	NM_001291694.2	ENSP00000388387	P1

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10909 AN: 152058 Hom.: 434 Cov.: 32

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.0750

GnomAD3 exomes AF: 0.0655 AC: 16454 AN: 251268 Hom.: 715 AF XY: 0.0669 AC XY: 9080 AN XY: 135806

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.0367

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0909

Gnomad OTH exome AF: 0.0836

GnomAD4 exome AF: 0.0843 AC: 123184 AN: 1461500 Hom.: 5787 Cov.: 31 AF XY: 0.0832 AC XY: 60526 AN XY: 727084

Gnomad4 AFR exome AF: 0.0613

Gnomad4 AMR exome AF: 0.0493

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.0388

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0943

Gnomad4 OTH exome AF: 0.0884

GnomAD4 genome AF: 0.0717 AC: 10913 AN: 152176 Hom.: 432 Cov.: 32 AF XY: 0.0678 AC XY: 5044 AN XY: 74414

Gnomad4 AFR AF: 0.0618

Gnomad4 AMR AF: 0.0671

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0378

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0926

Gnomad4 OTH AF: 0.0747

Alfa AF: 0.0909 Hom.: 569

Bravo AF: 0.0760

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.0997

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.5
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230444; hg19: chr3-15080696;