2-74873855-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000189.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK2	NM_000189.5	MANE Select	c.603C>T	p.Ile201Ile	synonymous	Exon 6 of 18	NP_000180.2
	HK2	NM_001371525.1		c.519C>T	p.Ile173Ile	synonymous	Exon 6 of 18	NP_001358454.1	E9PB90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK2	ENST00000290573.7	TSL:1 MANE Select	c.603C>T	p.Ile201Ile	synonymous	Exon 6 of 18	ENSP00000290573.2	P52789
	HK2	ENST00000409174.1	TSL:1	c.519C>T	p.Ile173Ile	synonymous	Exon 6 of 18	ENSP00000387140.1	E9PB90
	HK2	ENST00000912519.1		c.603C>T	p.Ile201Ile	synonymous	Exon 6 of 18	ENSP00000582578.1

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

GnomAD2 exomes AF: 0.00148 AC: 373 AN: 251422 AF XY: 0.00164

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33472

American (AMR) AF: 0.000291 AC: 13 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26126

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86234

European-Finnish (FIN) AF: 0.00146 AC: 78 AN: 53412

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00247 AC: 2740 AN: 1111544

Other (OTH) AF: 0.00243 AC: 147 AN: 60376

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

African (AFR) AF: 0.000458 AC: 19 AN: 41464

American (AMR) AF: 0.000524 AC: 8 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00127

EpiCase AF: 0.00158

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.9
DANN	Benign	0.72
PhyloP100		-1.8
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs146408073; hg19: chr2-75100982;