16-86567354-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005251.3(FOXC2):c.19G>A(p.Val7Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
FOXC2
NM_005251.3 missense
NM_005251.3 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 7.34
Genes affected
FOXC2 (HGNC:3801): (forkhead box C2) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the development of mesenchymal tissues. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FOXC2 | NM_005251.3 | c.19G>A | p.Val7Met | missense_variant | 1/1 | ENST00000649859.1 | NP_005242.1 | |
FOXC2-AS1 | NR_125795.1 | n.145+263C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FOXC2 | ENST00000649859.1 | c.19G>A | p.Val7Met | missense_variant | 1/1 | NM_005251.3 | ENSP00000497759.1 | |||
FOXC2-AS1 | ENST00000563280.3 | n.231+263C>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460700Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726680
GnomAD4 exome
AF:
AC:
3
AN:
1460700
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
726680
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 21, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. This missense change has been observed in individual(s) with FOXC2-related conditions (PMID: 30029678). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 7 of the FOXC2 protein (p.Val7Met). This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;M
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N
REVEL
Uncertain
Sift
Uncertain
.;D
Sift4G
Uncertain
.;D
Polyphen
D;D
Vest4
0.53
MutPred
Gain of disorder (P = 0.05);Gain of disorder (P = 0.05);
MVP
0.97
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at