NM_000189.5:c.2531G>A

Variant names:

• chr2-74889400-G-A
• rs2229629
• NM_000189.5:c.2531G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (6226 hom., cov: 32)
  • Exomes 𝑓: 0.032 (6068 hom.)
• Consequence: HK2 NM_000189.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.52
• Publications: 27 publications found

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]

ENSG00000309281 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3056076.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
HK2	NM_000189.5	c.2531G>A	p.Arg844Lys	missense_variant	Exon 17 of 18	ENST00000290573.7	NP_000180.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK2	ENST00000290573.7	c.2531G>A	p.Arg844Lys	missense_variant	Exon 17 of 18	1	NM_000189.5	ENSP00000290573.2
HK2	ENST00000409174.1	c.2447G>A	p.Arg816Lys	missense_variant	Exon 17 of 18	1		ENSP00000387140.1
ENSG00000309281	ENST00000840051.1	n.198-3755C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25638 AN: 152064 Hom.: 6210 Cov.: 32

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

GnomAD2 exomes AF: 0.0605 AC: 15183 AN: 251106 AF XY: 0.0504

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 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.: 32 AF XY: 0.0299 AC XY: 21716 AN XY: 727198

African (AFR) AF: 0.562 AC: 18786 AN: 33456

American (AMR) AF: 0.0313 AC: 1398 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 349 AN: 26136

East Asian (EAS) AF: 0.124 AC: 4922 AN: 39692

South Asian (SAS) AF: 0.0364 AC: 3140 AN: 86246

European-Finnish (FIN) AF: 0.00968 AC: 517 AN: 53412

Middle Eastern (MID) AF: 0.0477 AC: 275 AN: 5768

European-Non Finnish (NFE) AF: 0.0121 AC: 13439 AN: 1111958

Other (OTH) AF: 0.0535 AC: 3231 AN: 60388

GnomAD4 genome AF: 0.169 AC: 25698 AN: 152182 Hom.: 6226 Cov.: 32 AF XY: 0.164 AC XY: 12214 AN XY: 74412

African (AFR) AF: 0.544 AC: 22543 AN: 41454

American (AMR) AF: 0.0720 AC: 1101 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.118 AC: 612 AN: 5176

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4824

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 892 AN: 68022

Other (OTH) AF: 0.114 AC: 242 AN: 2116

Alfa AF: 0.0787 Hom.: 1276

Bravo AF: 0.191

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.00934 AC: 36

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: no assertion criteria provided

Submissions by phenotype

HK2-related disorder Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0011	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N;.
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
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	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.42
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229629; hg19: chr2-75116527; COSMIC: COSV51874292;