chr2-48359081-C-T

Variant names:

• chr2-48359081-C-T
• rs999946760
• NM_002158.4:c.572C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_002158.4(FOXN2):​c.572C>T​(p.Pro191Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,612,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P191A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FOXN2 NM_002158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• Publications: 0 publications found

Genes affected

FOXN2 (HGNC:5281): (forkhead box N2) This gene encodes a forkhead domain binding protein and may function in the transcriptional regulation of the human T-cell leukemia virus long terminal repeat. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002158.4. 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
	FOXN2	NM_002158.4	MANE Select	c.572C>T	p.Pro191Leu	missense	Exon 4 of 7	NP_002149.2
	FOXN2	NM_001375442.1		c.572C>T	p.Pro191Leu	missense	Exon 4 of 7	NP_001362371.1	P32314-1
	FOXN2	NM_001375443.1		c.572C>T	p.Pro191Leu	missense	Exon 3 of 6	NP_001362372.1	P32314-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN2	ENST00000340553.8	TSL:1 MANE Select	c.572C>T	p.Pro191Leu	missense	Exon 4 of 7	ENSP00000343633.3	P32314-1
	FOXN2	ENST00000872826.1		c.572C>T	p.Pro191Leu	missense	Exon 5 of 8	ENSP00000542885.1
	FOXN2	ENST00000872827.1		c.572C>T	p.Pro191Leu	missense	Exon 4 of 7	ENSP00000542886.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151508 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251028 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460990 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726828

African (AFR) AF: 0.0000897 AC: 3 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111538

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151508 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74008

African (AFR) AF: 0.0000729 AC: 3 AN: 41166

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.83		Loss of disorder (P = 0.0516)
MVP		0.99
MPC		0.13
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.66
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs999946760; hg19: chr2-48586220;