10-69369119-T-C

Variant names:

• chr10-69369119-T-C
• rs2305198
• NM_001358263.1:c.604-118T>C

Variant summary

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

The NM_001358263.1(HK1):​c.604-118T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 746,636 control chromosomes in the GnomAD database, including 63,615 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 0.45 (16868 hom., cov: 32)
  • Exomes 𝑓: 0.39 (46747 hom.)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 8 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.604-118T>C		intron_variant	Intron 8 of 20	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.592-118T>C		intron_variant	Intron 5 of 17	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.604-118T>C		intron_variant	Intron 8 of 20		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7	c.592-118T>C		intron_variant	Intron 5 of 17	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68097 AN: 152004 Hom.: 16829 Cov.: 32

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.388 AC: 230912 AN: 594514 Hom.: 46747 AF XY: 0.394 AC XY: 126148 AN XY: 319792

African (AFR) AF: 0.656 AC: 10883 AN: 16602

American (AMR) AF: 0.228 AC: 7979 AN: 34996

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 6964 AN: 20222

East Asian (EAS) AF: 0.290 AC: 9528 AN: 32852

South Asian (SAS) AF: 0.500 AC: 31750 AN: 63530

European-Finnish (FIN) AF: 0.435 AC: 20502 AN: 47158

Middle Eastern (MID) AF: 0.302 AC: 773 AN: 2558

European-Non Finnish (NFE) AF: 0.378 AC: 130397 AN: 344946

Other (OTH) AF: 0.383 AC: 12136 AN: 31650

GnomAD4 genome AF: 0.448 AC: 68187 AN: 152122 Hom.: 16868 Cov.: 32 AF XY: 0.449 AC XY: 33367 AN XY: 74340

African (AFR) AF: 0.658 AC: 27293 AN: 41502

American (AMR) AF: 0.291 AC: 4451 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1192 AN: 3472

East Asian (EAS) AF: 0.264 AC: 1363 AN: 5170

South Asian (SAS) AF: 0.487 AC: 2347 AN: 4820

European-Finnish (FIN) AF: 0.433 AC: 4585 AN: 10594

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25766 AN: 67970

Other (OTH) AF: 0.391 AC: 825 AN: 2110

Alfa AF: 0.392 Hom.: 51185

Bravo AF: 0.440

Asia WGS AF: 0.423 AC: 1469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.7
DANN	Benign	0.60
PhyloP100		0.010
Mutation Taster		=9/91	disease causing

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: rs2305198; hg19: chr10-71128875; COSMIC: COSV53867958; COSMIC: COSV53867958;