rs1555447237

chr15-96334573-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_021005.4(NR2F2):c.940T>C(p.Cys314Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR2F2 NM_021005.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.97

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 11 ACMG points.

• PM1: In a domain NR LBD (size 226) in uniprot entity COT2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_021005.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NR2F2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 15-96334573-T-C is Pathogenic according to our data. Variant chr15-96334573-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2F2	NM_021005.4	c.940T>C	p.Cys314Arg	missense_variant	2/3	ENST00000394166.8
NR2F2	NM_001145155.2	c.541T>C	p.Cys181Arg	missense_variant	2/3
NR2F2	NM_001145156.1	c.481T>C	p.Cys161Arg	missense_variant	2/3
NR2F2	NM_001145157.2	c.481T>C	p.Cys161Arg	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2F2	ENST00000394166.8	c.940T>C	p.Cys314Arg	missense_variant	2/3	1	NM_021005.4	P1
NR2F2	ENST00000421109.6	c.541T>C	p.Cys181Arg	missense_variant	2/3	1
NR2F2	ENST00000453270.2	c.481T>C	p.Cys161Arg	missense_variant	2/3	1
NR2F2	ENST00000394171.6	c.481T>C	p.Cys161Arg	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.5	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.96
MutPred		0.86		.;Loss of catalytic residue at L315 (P = 0.0134);.;.;
MVP		0.98
MPC		4.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.97

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: rs1555447237; hg19: chr15-96877802;