Genetic Variant HK2:p.Tyr9Phe (chr2-74834606-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000189.5(HK2):c.26A>T(p.Tyr9Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

HK2
NM_000189.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16

Variant links:

Genes affected

HK2 (HGNC:4923): (hexokinase 2) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, Apr 2009]

HK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15958348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK2	NM_000189.5 link	c.26A>T	p.Tyr9Phe	missense_variant	Exon 1 of 18	ENST00000290573.7	NP_000180.2	P52789
HK2	XM_005264280.3 link	c.26A>T	p.Tyr9Phe	missense_variant	Exon 1 of 18		XP_005264337.1
HK2	XM_011532807.3 link	c.26A>T	p.Tyr9Phe	missense_variant	Exon 1 of 17		XP_011531109.1
HK2	XM_017003945.3 link	c.26A>T	p.Tyr9Phe	missense_variant	Exon 1 of 17		XP_016859434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK2	ENST00000290573.7 link	c.26A>T	p.Tyr9Phe	missense_variant	Exon 1 of 18	1	NM_000189.5	ENSP00000290573.2		P52789

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249656

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26A>T (p.Y9F) alteration is located in exon 1 (coding exon 1) of the HK2 gene. This alteration results from a A to T substitution at nucleotide position 26, causing the tyrosine (Y) at amino acid position 9 to be replaced by a phenylalanine (F). 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

0.27

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.15

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.077

MetaRNN

Benign

0.16

MetaSVM

Uncertain

-0.031

MutationAssessor

Benign

0.85

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.33

Sift

Benign

0.76

Sift4G

Benign

0.48

Polyphen

0.0050

Vest4

0.37

MVP

0.75

MPC

0.38

ClinPred

0.26

GERP RS

2.8

Varity_R

0.087

gMVP

0.42

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over