Genetic Variant NR2F2:c.*2470G>T (chr15-96340092-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021005.4(NR2F2):c.*2470G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 152,036 control chromosomes in the GnomAD database, including 19,996 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 0.44 ( 19996 hom., cov: 32)

Exomes 𝑓: 0.20 ( 0 hom. )

Consequence

NR2F2
NM_021005.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.619

Publications

6 publications found

Variant links:

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]

NR2F2 Gene-Disease associations (from GenCC):

46,xx sex reversal 5
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
NR2F2 related multiple congenital anomalies/dysmorphic syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
congenital heart defects, multiple types, 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

NR2F2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NR2F2	NM_021005.4 link	c.*2470G>T	3_prime_UTR_variant	Exon 3 of 3	ENST00000394166.8	NP_066285.1	P24468-1F1D8R0
NR2F2	NM_001145155.2 link	c.*2470G>T	3_prime_UTR_variant	Exon 3 of 3		NP_001138627.1	P24468-2
NR2F2	NM_001145156.1 link	c.*2470G>T	3_prime_UTR_variant	Exon 3 of 3		NP_001138628.1	P24468-3
NR2F2	NM_001145157.2 link	c.*2470G>T	3_prime_UTR_variant	Exon 3 of 3		NP_001138629.1	P24468-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F2	ENST00000394166.8 link	c.*2470G>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_021005.4	ENSP00000377721.3		P24468-1
NR2F2	ENST00000394171.6 link	c.*2470G>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000377726.2		P24468-3

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66656

AN:

151908

Hom.:

19923

Cov.:

show subpopulations

Gnomad AFR

AF:

0.827

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.225

Gnomad OTH

AF:

0.405

GnomAD4 exome

AF:

0.200

AC:

AN:

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.439

AC:

66800

AN:

152026

Hom.:

19996

Cov.:

AF XY:

0.445

AC XY:

33032

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.828

AC:

34338

AN:

41480

American (AMR)

AF:

0.459

AC:

7026

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

658

AN:

3468

East Asian (EAS)

AF:

0.717

AC:

3710

AN:

5172

South Asian (SAS)

AF:

0.270

AC:

1297

AN:

4800

European-Finnish (FIN)

AF:

0.323

AC:

3410

AN:

10548

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.225

AC:

15296

AN:

67944

Other (OTH)

AF:

0.411

AC:

868

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1401

2801

4202

5602

7003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.307

Hom.:

17503

Bravo

AF:

0.475

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over