rs886775310

Variant names:

• chr16-86567459-T-G
• rs886775310
• NM_005251.3:c.124T>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.124T>G​(p.Ser42Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. S42C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXC2 NM_005251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.55
• 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=0.21505103).

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.124T>G	p.Ser42Ala	missense	Exon 1 of 1	NP_005242.1	Q99958
	FOXC2-AS1	NR_125795.1		n.145+158A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC2	ENST00000649859.1	MANE Select	c.124T>G	p.Ser42Ala	missense	Exon 1 of 1	ENSP00000497759.1	Q99958
	FOXC2-AS1	ENST00000809049.1		n.231A>C		non_coding_transcript_exon	Exon 1 of 2
	FOXC2-AS1	ENST00000563280.4	TSL:3	n.313+158A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Benign	0.13	T
Sift4G	Benign	0.36	T
Polyphen		0.037	B
Vest4		0.26
MutPred		0.26		Loss of glycosylation at S42 (P = 0.0029)
MVP		0.92
ClinPred		0.14	T
GERP RS		1.7
Varity_R		0.16
gMVP		0.51
Mutation Taster		=91/9	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: rs886775310; hg19: chr16-86601065;