2-74873855-C-T

Variant names:

• chr2-74873855-C-T
• rs146408073
• NM_000189.5:c.603C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000189.5(HK2):​c.603C>T​(p.Ile201Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,613,416 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: HK2 NM_000189.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.75

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-74873855-C-T is Benign according to our data. Variant chr2-74873855-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037590.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK2	NM_000189.5	c.603C>T	p.Ile201Ile	synonymous_variant	Exon 6 of 18	ENST00000290573.7	NP_000180.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK2	ENST00000290573.7	c.603C>T	p.Ile201Ile	synonymous_variant	Exon 6 of 18	1	NM_000189.5	ENSP00000290573.2
HK2	ENST00000409174.1	c.519C>T	p.Ile173Ile	synonymous_variant	Exon 6 of 18	1		ENSP00000387140.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00148 AC: 373 AN: 251422 Hom.: 0 AF XY: 0.00164 AC XY: 223 AN XY: 135892

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00212 AC: 3101 AN: 1461338 Hom.: 3 Cov.: 32 AF XY: 0.00210 AC XY: 1527 AN XY: 727000

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74340

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00127

EpiCase AF: 0.00158

EpiControl AF: 0.00261

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HK2-related disorder Benign:1

Feb 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.43
CADD	Benign	6.9
DANN	Benign	0.72

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: rs146408073; hg19: chr2-75100982;