15-96332307-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Moderate BP6_Moderate

The NM_021005.4(NR2F2):c.202A>G(p.Ser68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,430,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S68N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NR2F2 NM_021005.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.27

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NR2F2
• BP4: Computational evidence support a benign effect (MetaRNN=0.09483266).
• BP6: Variant 15-96332307-A-G is Benign according to our data. Variant chr15-96332307-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2569423.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.202A>G	p.Ser68Gly	missense_variant	1/3	ENST00000394166.8
NR2F2	NM_001145155.2	c.44-1769A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2F2	ENST00000394166.8	c.202A>G	p.Ser68Gly	missense_variant	1/3	1	NM_021005.4	P1
NR2F2	ENST00000421109.6	c.44-1769A>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000505 AC: 1 AN: 197998 Hom.: 0 AF XY: 0.00000933 AC XY: 1 AN XY: 107162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 26 AN: 1430626 Hom.: 0 Cov.: 31 AF XY: 0.0000183 AC XY: 13 AN XY: 709102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000237

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000627 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Benign	0.50
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.31
Sift	Benign	0.92	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.085
MutPred		0.18		Loss of glycosylation at S68 (P = 0.0129);
MVP		0.51
MPC		1.4
ClinPred		0.021	T
GERP RS		1.4
Varity_R		0.054
gMVP		0.066

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: rs766186920; hg19: chr15-96875536;