16-86567354-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V7A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FOXC2 NM_005251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

FOXC2-AS1 (HGNC:50665): (FOXC2 antisense RNA 1)

ACMG classification

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	UniProt
FOXC2	NM_005251.3	c.19G>A	p.Val7Met	missense_variant	1/1	ENST00000649859.1
FOXC2-AS1	NR_125795.1	n.145+263C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC2	ENST00000649859.1	c.19G>A	p.Val7Met	missense_variant	1/1		NM_005251.3	P1
FOXC2-AS1	ENST00000563280.3	n.231+263C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460700 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726680

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
Polyphen		1.0	D;D
Vest4		0.53
MutPred		0.21		Gain of disorder (P = 0.05);Gain of disorder (P = 0.05);
MVP		0.97
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.26
gMVP		0.65

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: rs1378523304; hg19: chr16-86600960; COSMIC: COSV100234076;