17-82520229-G-A

Variant names:

• chr17-82520229-G-A
• rs2044346650
• NM_004514.4:c.341G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004514.4(FOXK2):​c.341G>A​(p.Arg114His) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.341G>A	p.Arg114His	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.341G>A	p.Arg114His	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.341G>A	p.Arg114His	missense_variant	Exon 1 of 5		XP_047291876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXK2	ENST00000335255.10	c.341G>A	p.Arg114His	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.341G>A		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.253G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3
FOXK2	ENST00000570585.1	n.-65G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151706 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1167266 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 564196

African (AFR) AF: 0.00 AC: 0 AN: 23114

American (AMR) AF: 0.00 AC: 0 AN: 8734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15084

East Asian (EAS) AF: 0.00 AC: 0 AN: 26980

South Asian (SAS) AF: 0.00 AC: 0 AN: 36142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 967282

Other (OTH) AF: 0.00 AC: 0 AN: 46896

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151706 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74116

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

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67842

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.341G>A (p.R114H) alteration is located in exon 1 (coding exon 1) of the FOXK2 gene. This alteration results from a G to A substitution at nucleotide position 341, causing the arginine (R) at amino acid position 114 to be replaced by a histidine (H). 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	0.67
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.44
Sift	Benign	0.039	D
Sift4G	Benign	0.40	T
Polyphen		0.59	P
Vest4		0.47
MutPred		0.71		Gain of methylation at K118 (P = 0.0637);
MVP		0.72
MPC		2.5
ClinPred		0.92	D
GERP RS		0.63
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.51

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

Other links and lift over

dbSNP: rs2044346650; hg19: chr17-80478105;