16-86567496-G-A

Variant names:

• chr16-86567496-G-A
• NM_005251.3:c.161G>A

Variant summary

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

The NM_005251.3(FOXC2):​c.161G>A​(p.Arg54His) variant causes a missense change. 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: 4.57

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 rank	MANE	Protein	UniProt
FOXC2	NM_005251.3	c.161G>A	p.Arg54His	missense_variant	Exon 1 of 1	ENST00000649859.1	NP_005242.1
FOXC2-AS1	NR_125795.1	n.145+121C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC2	ENST00000649859.1	c.161G>A	p.Arg54His	missense_variant	Exon 1 of 1		NM_005251.3	ENSP00000497759.1
FOXC2-AS1	ENST00000563280.3	n.231+121C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161G>A (p.R54H) alteration is located in exon 1 (coding exon 1) of the FOXC2 gene. This alteration results from a G to A substitution at nucleotide position 161, causing the arginine (R) at amino acid position 54 to be replaced by a histidine (H). 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	0.18
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	.;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	.;D
Sift4G	Uncertain	0.017	.;D
Polyphen		0.57	P;P
Vest4		0.38
MutPred		0.24		Loss of phosphorylation at S55 (P = 0.1115);Loss of phosphorylation at S55 (P = 0.1115);
MVP		0.94
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.49
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-86601102; COSMIC: COSV100234352;