Genetic Variant FOXK2:p.Ala132Val (chr17-82520283-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004514.4(FOXK2):c.395C>T(p.Ala132Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXK2
NM_004514.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.58

Publications

0 publications found

Variant links:

Genes affected

FOXK2 (HGNC:6036): (forkhead box K2) The protein encoded by this gene contains a fork head DNA binding domain. This protein can bind to the purine-rich motifs of the HIV long terminal repeat (LTR), and to the similar purine-rich motif in the interleukin 2 (IL2) promoter. It may be involved in the regulation of viral and cellular promoter elements. [provided by RefSeq, Jul 2008]

FOXK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27075988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4 link	c.395C>T	p.Ala132Val	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2	Q01167-1
FOXK2	XM_047435919.1 link	c.395C>T	p.Ala132Val	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1 link	c.395C>T	p.Ala132Val	missense_variant	Exon 1 of 5		XP_047291876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXK2	ENST00000335255.10 link	c.395C>T	p.Ala132Val	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5	Q01167-1
FOXK2	ENST00000473637.6 link	n.395C>T		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2	Q01167-2
FOXK2	ENST00000527313.6 link	n.307C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3
FOXK2	ENST00000570585.1 link	n.-11C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1115172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

530366

African (AFR)

AF:

0.00

AC:

AN:

22634

American (AMR)

AF:

0.00

AC:

AN:

8304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14288

East Asian (EAS)

AF:

0.00

AC:

AN:

26238

South Asian (SAS)

AF:

0.00

AC:

AN:

25312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3196

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

934008

Other (OTH)

AF:

0.00

AC:

AN:

44386

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 16, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.395C>T (p.A132V) alteration is located in exon 1 (coding exon 1) of the FOXK2 gene. This alteration results from a C to T substitution at nucleotide position 395, causing the alanine (A) at amino acid position 132 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

Pathogenic

0.96

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PhyloP100

2.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.16

Sift

Benign

0.070

Sift4G

Benign

0.18

Polyphen

0.77

Vest4

0.21

MutPred

0.37

Loss of disorder (P = 0.1817);

MVP

0.27

MPC

1.6

ClinPred

0.96

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Varity_R

0.23

gMVP

0.49

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over