17-82519953-G-A

Variant names:

• chr17-82519953-G-A
• rs928998428
• NM_004514.4:c.65G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004514.4(FOXK2):​c.65G>A​(p.Gly22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,016,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000041 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.771
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24866062).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.65G>A	p.Gly22Asp	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.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.65G>A		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.-24G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000412 AC: 6 AN: 145498 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000681

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: 0.0000763

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000218 AC: 19 AN: 870626 Hom.: 0 Cov.: 27 AF XY: 0.0000222 AC XY: 9 AN XY: 404950

African (AFR) AF: 0.00 AC: 0 AN: 16618

American (AMR) AF: 0.00 AC: 0 AN: 2058

Ashkenazi Jewish (ASJ) AF: 0.000157 AC: 1 AN: 6366

East Asian (EAS) AF: 0.00 AC: 0 AN: 7228

South Asian (SAS) AF: 0.0000567 AC: 1 AN: 17628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1820

European-Non Finnish (NFE) AF: 0.0000216 AC: 17 AN: 785392

Other (OTH) AF: 0.00 AC: 0 AN: 29548

GnomAD4 genome AF: 0.0000412 AC: 6 AN: 145498 Hom.: 0 Cov.: 29 AF XY: 0.0000565 AC XY: 4 AN XY: 70734

African (AFR) AF: 0.00 AC: 0 AN: 40638

American (AMR) AF: 0.0000681 AC: 1 AN: 14690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000763 AC: 5 AN: 65546

Other (OTH) AF: 0.00 AC: 0 AN: 2008

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65G>A (p.G22D) 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 65, causing the glycine (G) at amino acid position 22 to be replaced by an aspartic acid (D). 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	0.24
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.77
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.22
Sift	Benign	0.10	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.33		Gain of relative solvent accessibility (P = 0.09);
MVP		0.77
MPC		1.4
ClinPred		0.13	T
GERP RS		0.063
PromoterAI		0.017	Neutral
Varity_R		0.078
gMVP		0.34
Mutation Taster		=97/3	polymorphism

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: rs928998428; hg19: chr17-80477829;