2-48346399-T-C

Variant names:

• chr2-48346399-T-C
• NM_002158.4:c.185T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002158.4(FOXN2):​c.185T>C​(p.Leu62Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXN2 NM_002158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN2	NM_002158.4	c.185T>C	p.Leu62Pro	missense_variant	Exon 3 of 7	ENST00000340553.8	NP_002149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN2	ENST00000340553.8	c.185T>C	p.Leu62Pro	missense_variant	Exon 3 of 7	1	NM_002158.4	ENSP00000343633.3
FOXN2	ENST00000413569.5	c.185T>C	p.Leu62Pro	missense_variant	Exon 2 of 5	3		ENSP00000388486.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185T>C (p.L62P) alteration is located in exon 3 (coding exon 1) of the FOXN2 gene. This alteration results from a T to C substitution at nucleotide position 185, causing the leucine (L) at amino acid position 62 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.79		Loss of stability (P = 0.0021);Loss of stability (P = 0.0021);
MVP		1.0
MPC		0.16
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr2-48573538;