3-15039189-G-C

Position:

• chr3-15039189-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001291694.2(NR2C2):​c.1578G>C​(p.Gln526His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: NR2C2 NM_001291694.2 missense
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3860642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2C2	NM_001291694.2	c.1578G>C	p.Gln526His	missense_variant	13/14	ENST00000425241.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2C2	ENST00000425241.6	c.1578G>C	p.Gln526His	missense_variant	13/14	2	NM_001291694.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.65	D;.;D;D;.;D;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	.;.;.;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.1	L;.;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N;N;N;N;.;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.074	T;T;T;T;.;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		0.68	P;.;P;P;.;.;.
Vest4		0.41
MutPred		0.58		Gain of glycosylation at Y528 (P = 0.0503);.;Gain of glycosylation at Y528 (P = 0.0503);Gain of glycosylation at Y528 (P = 0.0503);.;.;.;
MVP		0.69
MPC		1.0
ClinPred		0.29	T
GERP RS		3.0
Varity_R		0.52
gMVP		0.70

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;