10-69292304-G-C

Variant names:

• chr10-69292304-G-C
• rs192516988
• ENST00000464803.6:c.74G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001322365.2(HK1):​c.74G>C​(p.Arg25Pro) 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. 10/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HK1 NM_001322365.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05506882).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322365.2. 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.28-3329G>C		intron	N/A	NP_001345192.1	P19367-3
	HK1	NM_001322365.2		c.74G>C	p.Arg25Pro	missense	Exon 5 of 23	NP_001309294.1
	HK1	NM_001322364.2		c.28-3329G>C		intron	N/A	NP_001309293.1	P19367-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000464803.6	TSL:1	c.74G>C	p.Arg25Pro	missense	Exon 5 of 7	ENSP00000496531.1	A0A2R8Y7T9
	HK1	ENST00000643399.2	MANE Plus Clinical	c.28-3329G>C		intron	N/A	ENSP00000494664.1	P19367-3
	HK1	ENST00000480047.5	TSL:1	n.332-3329G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.16
DANN	Benign	0.095
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00027	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.6
MutPred		0.49		Loss of MoRF binding (P = 0.0012)
GERP RS		-2.1
Mutation Taster		=96/4	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs192516988; hg19: chr10-71052060;