2-74872350-A-T

Variant names:

• chr2-74872350-A-T
• rs2229621
• NM_000189.5:c.426A>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000189.5(HK2):​c.426A>T​(p.Gln142His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,613,314 control chromosomes in the GnomAD database, including 27,443 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (2797 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24646 hom.)
• Consequence: HK2 NM_000189.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.13

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.597374E-4).
• BP6: Variant 2-74872350-A-T is Benign according to our data. Variant chr2-74872350-A-T is described in ClinVar as [Benign]. Clinvar id is 3056615.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK2	NM_000189.5	c.426A>T	p.Gln142His	missense_variant	Exon 4 of 18	ENST00000290573.7	NP_000180.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK2	ENST00000290573.7	c.426A>T	p.Gln142His	missense_variant	Exon 4 of 18	1	NM_000189.5	ENSP00000290573.2
HK2	ENST00000409174.1	c.342A>T	p.Gln114His	missense_variant	Exon 4 of 18	1		ENSP00000387140.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28687 AN: 151918 Hom.: 2790 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0947

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.179 AC: 45134 AN: 251490 Hom.: 4117 AF XY: 0.184 AC XY: 24957 AN XY: 135916

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.173

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.182 AC: 265258 AN: 1461278 Hom.: 24646 Cov.: 34 AF XY: 0.182 AC XY: 132501 AN XY: 726986

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.189 AC: 28716 AN: 152036 Hom.: 2797 Cov.: 32 AF XY: 0.191 AC XY: 14200 AN XY: 74302

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.188

Alfa AF: 0.184 Hom.: 844

Bravo AF: 0.183

TwinsUK AF: 0.184 AC: 683

ALSPAC AF: 0.180 AC: 694

ESP6500AA AF: 0.202 AC: 891

ESP6500EA AF: 0.185 AC: 1590

ExAC AF: 0.183 AC: 22187

Asia WGS AF: 0.179 AC: 621 AN: 3478

EpiCase AF: 0.183

EpiControl AF: 0.178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HK2-related disorder Benign:1

Oct 28, 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	0.092
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.0
DANN	Benign	0.86
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.00086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.095
Sift	Benign	0.14	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.68	P;.
Vest4		0.17
MutPred		0.19		Gain of methylation at K144 (P = 0.1003);.;
MPC		0.50
ClinPred		0.017	T
GERP RS		-8.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.54

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

Other links and lift over

dbSNP: rs2229621; hg19: chr2-75099477; COSMIC: COSV51879371; COSMIC: COSV51879371;