3-15017449-A-G

Position:

• chr3-15017449-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.376+1195A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,204 control chromosomes in the GnomAD database, including 1,419 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 0.12 (1419 hom., cov: 32)
• Consequence: NR2C2 NM_001291694.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.448

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]

NR2C2 (HGNC:):

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=-0.58).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2C2	NM_001291694.2	c.376+1195A>G		intron_variant		ENST00000425241.6	NP_001278623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2C2	ENST00000425241.6	c.376+1195A>G		intron_variant		2	NM_001291694.2	ENSP00000388387.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18881 AN: 152086 Hom.: 1421 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0981

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.124 AC: 18864 AN: 152204 Hom.: 1419 Cov.: 32 AF XY: 0.121 AC XY: 8983 AN XY: 74420

Gnomad4 AFR AF: 0.0337

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0970

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.154

Alfa AF: 0.158 Hom.: 2007

Bravo AF: 0.122

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	10
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3773480; hg19: chr3-15058956; COSMIC: COSV60148593; COSMIC: COSV60148593;