Genetic Variant NM_002158.4:c.724G>A (chr2-48373312-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002158.4(FOXN2):c.724G>A(p.Ala242Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FOXN2
NM_002158.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.80

Publications

0 publications found

Variant links:

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]

FOXN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03722903).

BP6

Variant 2-48373312-G-A is Benign according to our data. Variant chr2-48373312-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3516844.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXN2	NM_002158.4	MANE Select	c.724G>A	p.Ala242Thr	missense	Exon 6 of 7	NP_002149.2
FOXN2	NM_001375442.1		c.724G>A	p.Ala242Thr	missense	Exon 6 of 7	NP_001362371.1	P32314-1
FOXN2	NM_001375443.1		c.724G>A	p.Ala242Thr	missense	Exon 5 of 6	NP_001362372.1	P32314-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXN2	ENST00000340553.8	TSL:1 MANE Select	c.724G>A	p.Ala242Thr	missense	Exon 6 of 7	ENSP00000343633.3	P32314-1
FOXN2	ENST00000872826.1		c.724G>A	p.Ala242Thr	missense	Exon 7 of 8	ENSP00000542885.1
FOXN2	ENST00000872827.1		c.724G>A	p.Ala242Thr	missense	Exon 6 of 7	ENSP00000542886.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000424

AC:

AN:

235650

AF XY:

0.00000780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440704

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717298

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31948

American (AMR)

AF:

0.00

AC:

AN:

40810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25714

East Asian (EAS)

AF:

0.00

AC:

AN:

38504

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102032

Other (OTH)

AF:

0.00

AC:

AN:

59506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.098

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.53

M_CAP

Benign

0.056

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-1.9

PhyloP100

2.8

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.42

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.25

MutPred

0.42

Loss of helix (P = 0.0068)

MVP

0.70

MPC

0.017

ClinPred

0.041

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.36

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over