chr16-86567686-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005251.3(FOXC2):​c.351G>C​(p.Gln117His) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q117Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

FOXC2
NM_005251.3 missense

Scores

14
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.93

Publications

0 publications found
Variant links:
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]
FOXC2-AS1 (HGNC:50665): (FOXC2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXC2NM_005251.3 linkc.351G>C p.Gln117His missense_variant Exon 1 of 1 ENST00000649859.1 NP_005242.1 Q99958
FOXC2-AS1NR_125795.1 linkn.76C>G non_coding_transcript_exon_variant Exon 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXC2ENST00000649859.1 linkc.351G>C p.Gln117His missense_variant Exon 1 of 1 NM_005251.3 ENSP00000497759.1 Q99958

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41460
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5164
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H;H
PhyloP100
3.9
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-4.7
.;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
.;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.93
Gain of ubiquitination at K113 (P = 0.0898);Gain of ubiquitination at K113 (P = 0.0898);
MVP
0.98
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.98
gMVP
0.96
Mutation Taster
=15/85
disease causing

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

Other links and lift over

dbSNP: rs886038560; hg19: chr16-86601292; API