16-86567414-G-C

Position:

• chr16-86567414-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005251.3(FOXC2):​c.79G>C​(p.Ala27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXC2 NM_005251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXC2	NM_005251.3	c.79G>C	p.Ala27Pro	missense_variant	1/1	ENST00000649859.1	NP_005242.1
FOXC2-AS1	NR_125795.1	n.145+203C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXC2	ENST00000649859.1	c.79G>C	p.Ala27Pro	missense_variant	1/1		NM_005251.3	ENSP00000497759.1
FOXC2-AS1	ENST00000563280.3	n.231+203C>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.79G>C (p.A27P) alteration is located in exon 1 (coding exon 1) of the FOXC2 gene. This alteration results from a G to C substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	0.091
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.3	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	.;N
REVEL	Uncertain	0.58
Sift	Benign	0.11	.;T
Sift4G	Benign	0.31	.;T
Polyphen		0.70	P;P
Vest4		0.52
MutPred		0.35		Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);
MVP		0.93
ClinPred		0.75	D
GERP RS		3.8
Varity_R		0.45
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: rs906672065; hg19: chr16-86601020;