rs878855066

Positions:

• chr15-96334342-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_021005.4(NR2F2):​c.709C>T​(p.Gln237Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR2F2 NM_021005.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

NR2F2 (HGNC:7976): (nuclear receptor subfamily 2 group F member 2) This gene encodes a member of the steroid thyroid hormone superfamily of nuclear receptors. The encoded protein is a ligand inducible transcription factor that is involved in the regulation of many different genes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2F2	NM_021005.4	c.709C>T	p.Gln237Ter	stop_gained	2/3	ENST00000394166.8	NP_066285.1
NR2F2	NM_001145155.2	c.310C>T	p.Gln104Ter	stop_gained	2/3		NP_001138627.1
NR2F2	NM_001145156.1	c.250C>T	p.Gln84Ter	stop_gained	2/3		NP_001138628.1
NR2F2	NM_001145157.2	c.250C>T	p.Gln84Ter	stop_gained	2/3		NP_001138629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2F2	ENST00000394166.8	c.709C>T	p.Gln237Ter	stop_gained	2/3	1	NM_021005.4	ENSP00000377721	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital heart defects, multiple types, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2016

This sequence change creates a premature translational stop signal at codon 237 (p.Gln237*) of the NR2F2 gene. It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in NR2F2 are not necessarily pathogenic (PMID: 24702954), and the clinical significance of this variant is uncertain at this time. For these reasons, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.96
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs878855066; hg19: chr15-96877571;