Genetic Variant FOXK2:p.Ser461Leu (chr17-82586006-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004514.4(FOXK2):c.1382C>T(p.Ser461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000423 in 1,612,802 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

FOXK2
NM_004514.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

Publications

3 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:

ENSG00000262147 (HGNC:58306):

ENSG00000262147 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10065967).

BS2

High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4 link	c.1382C>T	p.Ser461Leu	missense_variant	Exon 7 of 9	ENST00000335255.10	NP_004505.2	Q01167-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXK2	ENST00000335255.10 link	c.1382C>T	p.Ser461Leu	missense_variant	Exon 7 of 9	1	NM_004514.4	ENSP00000335677.5		Q01167-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000293

AC:

AN:

249406

AF XY:

0.000340

show subpopulations

Gnomad AFR exome

AF:

0.000497

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000384

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000416

AC:

607

AN:

1460466

Hom.:

Cov.:

AF XY:

0.000423

AC XY:

307

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000960

AC:

AN:

52096

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000453

AC:

504

AN:

1111940

Other (OTH)

AF:

0.000414

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000492

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41576

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000388

Hom.:

Bravo

AF:

0.000589

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000298

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1382C>T (p.S461L) alteration is located in exon 7 (coding exon 7) of the FOXK2 gene. This alteration results from a C to T substitution at nucleotide position 1382, causing the serine (S) at amino acid position 461 to be replaced by a leucine (L). 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

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.1

PhyloP100

5.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.096

Sift4G

Benign

0.21

Polyphen

0.38

Vest4

0.38

MVP

0.59

MPC

0.11

ClinPred

0.018

GERP RS

4.3

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.27

Mutation Taster

=85/15

polymorphism

(source)

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

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17-82586006-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over