Variant rs2229629 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000189.5(HK2):c.2531G>A(p.Arg844Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,613,952 control chromosomes in the GnomAD database, including 12,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.17 ( 6226 hom., cov: 32)

Exomes 𝑓: 0.032 ( 6068 hom. )

Consequence

HK2
NM_000189.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.52

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010570288).

BP6

Variant 2-74889400-G-A is Benign according to our data. Variant chr2-74889400-G-A is described in ClinVar as [Benign]. Clinvar id is 3056076.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK2	NM_000189.5 linkuse as main transcript	c.2531G>A	p.Arg844Lys	missense_variant	17/18	ENST00000290573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK2	ENST00000290573.7 linkuse as main transcript	c.2531G>A	p.Arg844Lys	missense_variant	17/18	1	NM_000189.5	P1
HK2	ENST00000409174.1 linkuse as main transcript	c.2447G>A	p.Arg816Lys	missense_variant	17/18	1

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25638

AN:

152064

Hom.:

6210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.544

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0722

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.0412

Gnomad FIN

AF:

0.00537

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.115

GnomAD3 exomes

AF:

0.0605

AC:

15183

AN:

251106

Hom.:

2697

AF XY:

0.0504

AC XY:

6844

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.555

Gnomad AMR exome

AF:

0.0265

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.0351

Gnomad FIN exome

AF:

0.00853

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.0329

GnomAD4 exome

AF:

0.0315

AC:

46057

AN:

1461770

Hom.:

6068

Cov.:

AF XY:

0.0299

AC XY:

21716

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.562

Gnomad4 AMR exome

AF:

0.0313

Gnomad4 ASJ exome

AF:

0.0134

Gnomad4 EAS exome

AF:

0.124

Gnomad4 SAS exome

AF:

0.0364

Gnomad4 FIN exome

AF:

0.00968

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.0535

GnomAD4 genome

AF:

0.169

AC:

25698

AN:

152182

Hom.:

6226

Cov.:

AF XY:

0.164

AC XY:

12214

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.544

Gnomad4 AMR

AF:

0.0720

Gnomad4 ASJ

AF:

0.0132

Gnomad4 EAS

AF:

0.118

Gnomad4 SAS

AF:

0.0408

Gnomad4 FIN

AF:

0.00537

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.0787

Hom.:

1276

Bravo

AF:

0.191

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.525

AC:

2314

ESP6500EA

AF:

0.0123

AC:

106

ExAC

AF:

0.0702

AC:

8519

Asia WGS

AF:

0.0920

AC:

320

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HK2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.0

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.75

PROVEAN

Benign

1.6

N;N

REVEL

Uncertain

0.31

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.084

MPC

0.41

ClinPred

0.012

GERP RS

5.0

Varity_R

0.24

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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