2-74854341-G-A

Variant names:

• chr2-74854341-G-A
• NM_000189.5:c.112G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000189.5(HK2):​c.112G>A​(p.Glu38Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HK2 NM_000189.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK2	NM_000189.5	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 18	ENST00000290573.7	NP_000180.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK2	ENST00000290573.7	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 18	1	NM_000189.5	ENSP00000290573.2
HK2	ENST00000409174.1	c.28G>A	p.Glu10Lys	missense_variant	Exon 2 of 18	1		ENSP00000387140.1
HK2	ENST00000472302.1	n.9G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112G>A (p.E38K) alteration is located in exon 2 (coding exon 2) of the HK2 gene. This alteration results from a G to A substitution at nucleotide position 112, causing the glutamic acid (E) at amino acid position 38 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.36	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.31	B;.
Vest4		0.50
MutPred		0.50		Gain of MoRF binding (P = 0.0013);.;
MVP		0.92
MPC		0.50
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.65
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-75081468;