rs2394538

Variant names:

• chr10-69273941-T-C
• rs2394538
• ENST00000464803.6:c.-196+2845T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001322365.2(HK1):​c.-196+2845T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,064 control chromosomes in the GnomAD database, including 7,343 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7343 hom., cov: 32)
• Consequence: HK1 NM_001322365.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 79

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

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

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	NM_001322365.2		c.-196+2845T>C		intron	N/A	NP_001309294.1
	HK1	NM_001322364.2		c.-74+3833T>C		intron	N/A	NP_001309293.1
	HK1	NM_033497.3		c.-196+3833T>C		intron	N/A	NP_277032.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000464803.6	TSL:1	c.-196+2845T>C		intron	N/A	ENSP00000496531.1
	HK1	ENST00000480047.5	TSL:1	n.109+3833T>C		intron	N/A
	HK1	ENST00000436817.6	TSL:5	c.-196+3833T>C		intron	N/A	ENSP00000415949.2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43982 AN: 151946 Hom.: 7341 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.331

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.289 AC: 43988 AN: 152064 Hom.: 7343 Cov.: 32 AF XY: 0.291 AC XY: 21657 AN XY: 74352

African (AFR) AF: 0.131 AC: 5448 AN: 41512

American (AMR) AF: 0.422 AC: 6436 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3470

East Asian (EAS) AF: 0.564 AC: 2917 AN: 5170

South Asian (SAS) AF: 0.243 AC: 1172 AN: 4814

European-Finnish (FIN) AF: 0.306 AC: 3226 AN: 10550

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22412 AN: 67968

Other (OTH) AF: 0.330 AC: 696 AN: 2110

Alfa AF: 0.314 Hom.: 4100

Bravo AF: 0.296

Asia WGS AF: 0.412 AC: 1429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.5
DANN	Benign	0.70
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2394538; hg19: chr10-71033697;