rs2230444

Variant names:

• chr3-15039189-G-A
• rs2230444
• NM_001291694.2:c.1578G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001291694.2(NR2C2):​c.1578G>A​(p.Gln526Gln) 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
• Publications: 7 publications found

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]

MRPS25 Gene-Disease associations (from GenCC):

• mitochondrial encephalomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• combined oxidative phosphorylation deficiency 50

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291694.2. 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
	NR2C2	NM_001291694.2	MANE Select	c.1578G>A	p.Gln526Gln	synonymous	Exon 13 of 14	NP_001278623.1
	NR2C2	NM_003298.5		c.1635G>A	p.Gln545Gln	synonymous	Exon 14 of 15	NP_003289.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C2	ENST00000425241.6	TSL:2 MANE Select	c.1578G>A	p.Gln526Gln	synonymous	Exon 13 of 14	ENSP00000388387.1
	NR2C2	ENST00000323373.10	TSL:1	c.1635G>A	p.Gln545Gln	synonymous	Exon 14 of 15	ENSP00000320447.6
	NR2C2	ENST00000617312.4	TSL:1	c.1635G>A	p.Gln545Gln	synonymous	Exon 13 of 14	ENSP00000483059.1

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

GnomAD2 exomes AF: 0.0655 AC: 16454 AN: 251268 AF XY: 0.0669

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 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

African (AFR) AF: 0.0613 AC: 2051 AN: 33474

American (AMR) AF: 0.0493 AC: 2206 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3680 AN: 26136

East Asian (EAS) AF: 0.00126 AC: 50 AN: 39700

South Asian (SAS) AF: 0.0388 AC: 3345 AN: 86254

European-Finnish (FIN) AF: 0.0210 AC: 1121 AN: 53418

Middle Eastern (MID) AF: 0.0891 AC: 514 AN: 5768

European-Non Finnish (NFE) AF: 0.0943 AC: 104879 AN: 1111646

Other (OTH) AF: 0.0884 AC: 5338 AN: 60384

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

African (AFR) AF: 0.0618 AC: 2565 AN: 41490

American (AMR) AF: 0.0671 AC: 1025 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0378 AC: 182 AN: 4818

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10606

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0926 AC: 6300 AN: 68008

Other (OTH) AF: 0.0747 AC: 158 AN: 2114

Alfa AF: 0.0888 Hom.: 722

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.5
DANN	Benign	0.60
PhyloP100		2.4
Mutation Taster		=96/4	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: rs2230444; hg19: chr3-15080696; COSMIC: COSV108113214; COSMIC: COSV108113214;