2-48346279-C-T

Variant names:

• chr2-48346279-C-T
• rs1671094577
• NM_002158.4:c.65C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002158.4(FOXN2):​c.65C>T​(p.Ala22Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOXN2 NM_002158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33834666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN2	NM_002158.4	c.65C>T	p.Ala22Val	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.65C>T	p.Ala22Val	missense_variant	Exon 3 of 7	1	NM_002158.4	ENSP00000343633.3
FOXN2	ENST00000413569.5	c.65C>T	p.Ala22Val	missense_variant	Exon 2 of 5	3		ENSP00000388486.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>T (p.A22V) alteration is located in exon 3 (coding exon 1) of the FOXN2 gene. This alteration results from a C to T substitution at nucleotide position 65, causing the alanine (A) at amino acid position 22 to be replaced by a valine (V). 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	Benign	0.091
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.3	.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.96	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.68	.;P
Vest4		0.32
MutPred		0.32		Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);
MVP		0.97
MPC		0.018
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1671094577; hg19: chr2-48573418;