16-86567496-G-C

Variant names:

• chr16-86567496-G-C
• rs746195395
• NM_005251.3:c.161G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005251.3(FOXC2):​c.161G>C​(p.Arg54Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,578 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOXC2 NM_005251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC2	NM_005251.3	MANE Select	c.161G>C	p.Arg54Pro	missense	Exon 1 of 1	NP_005242.1	Q99958
	FOXC2-AS1	NR_125795.1		n.145+121C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC2	ENST00000649859.1	MANE Select	c.161G>C	p.Arg54Pro	missense	Exon 1 of 1	ENSP00000497759.1	Q99958
	FOXC2-AS1	ENST00000809049.1		n.194C>G		non_coding_transcript_exon	Exon 1 of 2
	FOXC2-AS1	ENST00000563280.4	TSL:3	n.313+121C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461578 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.57
Sift	Benign	0.080	T
Sift4G	Benign	0.091	T
Polyphen		0.38	B
Vest4		0.26
MutPred		0.29		Gain of glycosylation at R54 (P = 0.0234)
MVP		0.94
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.76
gMVP		0.84
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs746195395; hg19: chr16-86601102;