chr15-96332200-C-G
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_021005.4(NR2F2):āc.95C>Gā(p.Pro32Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000823 in 1,336,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 31)
Exomes š: 0.0000068 ( 0 hom. )
Consequence
NR2F2
NM_021005.4 missense
NM_021005.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 5.51
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NR2F2. . Gene score misZ 3.5964 (greater than the threshold 3.09). Trascript score misZ 4.1992 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart defects, multiple types, 4, NR2F2 related multiple congenital anomalies/dysmorphic syndrome.
BS2
High AC in GnomAdExome4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NR2F2 | NM_021005.4 | c.95C>G | p.Pro32Arg | missense_variant | 1/3 | ENST00000394166.8 | NP_066285.1 | |
NR2F2 | NM_001145155.2 | c.44-1876C>G | intron_variant | NP_001138627.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NR2F2 | ENST00000394166.8 | c.95C>G | p.Pro32Arg | missense_variant | 1/3 | 1 | NM_021005.4 | ENSP00000377721 | P1 | |
NR2F2 | ENST00000421109.6 | c.44-1876C>G | intron_variant | 1 | ENSP00000401674 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151476Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000675 AC: 8AN: 1184576Hom.: 0 Cov.: 30 AF XY: 0.00000520 AC XY: 3AN XY: 577330
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GnomAD4 genome AF: 0.0000198 AC: 3AN: 151476Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 73972
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 26, 2024 | The c.95C>G (p.P32R) alteration is located in exon 1 (coding exon 1) of the NR2F2 gene. This alteration results from a C to G substitution at nucleotide position 95, causing the proline (P) at amino acid position 32 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Congenital heart defects, multiple types, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 28, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NR2F2 protein function. This variant has not been reported in the literature in individuals affected with NR2F2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 32 of the NR2F2 protein (p.Pro32Arg). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of methylation at P32 (P = 0.0177);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at