17-82520153-G-T

Variant names:

• chr17-82520153-G-T
• rs959597916
• NM_004514.4:c.265G>T

Variant summary

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

The NM_004514.4(FOXK2):​c.265G>T​(p.Gly89Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,365,112 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• 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.265G>T	p.Gly89Cys	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.265G>T	p.Gly89Cys	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.265G>T	p.Gly89Cys	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.265G>T	p.Gly89Cys	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.265G>T		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.177G>T		non_coding_transcript_exon_variant	Exon 1 of 3	3
FOXK2	ENST00000570585.1	n.-141G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1365112 Hom.: 0 Cov.: 33 AF XY: 0.00000147 AC XY: 1 AN XY: 678612

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

African (AFR) AF: 0.00 AC: 0 AN: 28210

American (AMR) AF: 0.00 AC: 0 AN: 33510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23472

East Asian (EAS) AF: 0.00 AC: 0 AN: 31170

South Asian (SAS) AF: 0.00 AC: 0 AN: 75748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1064270

Other (OTH) AF: 0.0000181 AC: 1 AN: 55328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.004626), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.37
MutPred		0.49		Loss of sheet (P = 0.0104);
MVP		0.75
MPC		1.5
ClinPred		0.66	D
GERP RS		0.32
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.22
gMVP		0.42
Mutation Taster		=86/14	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: rs959597916; hg19: chr17-80478029;