10-69382664-G-C

Variant names:

• chr10-69382664-G-C
• rs748235
• NM_001358263.1:c.1455G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000188.3(HK1):​c.1443G>C​(p.Lys481Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K481K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HK1 NM_000188.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.894
• Publications: 29 publications found

Genes affected

HK1 (HGNC:4922): (hexokinase 1) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific. [provided by RefSeq, Apr 2016]

HK1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with visual defects and brain anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 79

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• non-spherocytic hemolytic anemia due to hexokinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 4G

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37756994).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000188.3. 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
	HK1	NM_001358263.1	MANE Plus Clinical	c.1455G>C	p.Lys485Asn	missense	Exon 13 of 21	NP_001345192.1	P19367-3
	HK1	NM_000188.3	MANE Select	c.1443G>C	p.Lys481Asn	missense	Exon 10 of 18	NP_000179.2	P19367-1
	HK1	NM_001322365.2		c.1548G>C	p.Lys516Asn	missense	Exon 15 of 23	NP_001309294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000643399.2	MANE Plus Clinical	c.1455G>C	p.Lys485Asn	missense	Exon 13 of 21	ENSP00000494664.1	P19367-3
	HK1	ENST00000359426.7	TSL:1 MANE Select	c.1443G>C	p.Lys481Asn	missense	Exon 10 of 18	ENSP00000352398.6	P19367-1
	HK1	ENST00000934397.1		c.1443G>C	p.Lys481Asn	missense	Exon 10 of 19	ENSP00000604456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.47	N
PhyloP100		-0.89
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.36
Sift	Benign	0.55	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.72
ClinPred		0.10	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.78
Mutation Taster		=63/37	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: rs748235; hg19: chr10-71142420;