rs2229622

chr2-74874327-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000189.5(HK2):c.753T>C(p.Asp251=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,760 control chromosomes in the GnomAD database, including 42,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (8487 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34471 hom.)
• Consequence: HK2 NM_000189.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.30

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-74874327-T-C is Benign according to our data. Variant chr2-74874327-T-C is described in ClinVar as [Benign]. Clinvar id is 3059165.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK2	NM_000189.5	c.753T>C	p.Asp251=	synonymous_variant	7/18	ENST00000290573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK2	ENST00000290573.7	c.753T>C	p.Asp251=	synonymous_variant	7/18	1	NM_000189.5	P1
HK2	ENST00000409174.1	c.669T>C	p.Asp223=	synonymous_variant	7/18	1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44955 AN: 151878 Hom.: 8456 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.222 AC: 55851 AN: 251216 Hom.: 7312 AF XY: 0.219 AC XY: 29741 AN XY: 135788

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.207 AC: 302233 AN: 1461764 Hom.: 34471 Cov.: 35 AF XY: 0.206 AC XY: 149710 AN XY: 727178

Gnomad4 AFR exome AF: 0.555

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.349

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.296 AC: 45038 AN: 151996 Hom.: 8487 Cov.: 32 AF XY: 0.296 AC XY: 21986 AN XY: 74280

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.260

Alfa AF: 0.235 Hom.: 2602

Bravo AF: 0.304

Asia WGS AF: 0.266 AC: 924 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.189

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HK2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 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
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.66
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2229622; hg19: chr2-75101454; COSMIC: COSV51873005;