16-86567443-C-G

Variant names:

• chr16-86567443-C-G
• rs138318843
• NM_005251.3:c.108C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005251.3(FOXC2):​c.108C>G​(p.Ser36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. S36S) has been classified as Benign.

• 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: 0.521
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2160205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC2	NM_005251.3	c.108C>G	p.Ser36Arg	missense_variant	Exon 1 of 1	ENST00000649859.1	NP_005242.1
FOXC2-AS1	NR_125795.1	n.145+174G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC2	ENST00000649859.1	c.108C>G	p.Ser36Arg	missense_variant	Exon 1 of 1		NM_005251.3	ENSP00000497759.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460990 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726848

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		0.52
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.24
Sift	Uncertain	0.0080	.;D
Sift4G	Uncertain	0.050	.;T
Polyphen		0.45	P;P
Vest4		0.19
MutPred		0.30		Loss of glycosylation at S36 (P = 0.0057);Loss of glycosylation at S36 (P = 0.0057);
MVP		0.90
ClinPred		0.39	T
GERP RS		2.0
Varity_R		0.22
gMVP		0.65
Mutation Taster		=88/12	polymorphism

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: rs138318843; hg19: chr16-86601049;