rs906216

Variant names:

• chr10-69338439-G-T
• rs906216
• NM_001358263.1:c.76-5388G>T

Variant summary

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

The NM_000188.3(HK1):​c.64-5388G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,257,506 control chromosomes in the GnomAD database, including 124,332 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 0.46 (17262 hom., cov: 31)
  • Exomes 𝑓: 0.44 (107070 hom.)
• Consequence: HK1 NM_000188.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

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.76-5388G>T		intron	N/A	NP_001345192.1	P19367-3
	HK1	NM_000188.3	MANE Select	c.64-5388G>T		intron	N/A	NP_000179.2	P19367-1
	HK1	NM_001322365.2		c.169-5388G>T		intron	N/A	NP_001309294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000643399.2	MANE Plus Clinical	c.76-5388G>T		intron	N/A	ENSP00000494664.1	P19367-3
	HK1	ENST00000359426.7	TSL:1 MANE Select	c.64-5388G>T		intron	N/A	ENSP00000352398.6	P19367-1
	HK1	ENST00000464803.6	TSL:1	c.169-5388G>T		intron	N/A	ENSP00000496531.1	A0A2R8Y7T9

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69547 AN: 151744 Hom.: 17237 Cov.: 31

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.435 AC: 480965 AN: 1105646 Hom.: 107070 Cov.: 32 AF XY: 0.433 AC XY: 232751 AN XY: 537300

African (AFR) AF: 0.647 AC: 15400 AN: 23818

American (AMR) AF: 0.213 AC: 5638 AN: 26494

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 4952 AN: 13948

East Asian (EAS) AF: 0.150 AC: 1869 AN: 12426

South Asian (SAS) AF: 0.378 AC: 27106 AN: 71794

European-Finnish (FIN) AF: 0.425 AC: 5075 AN: 11938

Middle Eastern (MID) AF: 0.309 AC: 1167 AN: 3782

European-Non Finnish (NFE) AF: 0.447 AC: 403323 AN: 901356

Other (OTH) AF: 0.410 AC: 16435 AN: 40090

GnomAD4 genome AF: 0.458 AC: 69622 AN: 151860 Hom.: 17262 Cov.: 31 AF XY: 0.453 AC XY: 33577 AN XY: 74202

African (AFR) AF: 0.628 AC: 26001 AN: 41382

American (AMR) AF: 0.317 AC: 4839 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1223 AN: 3464

East Asian (EAS) AF: 0.158 AC: 816 AN: 5160

South Asian (SAS) AF: 0.360 AC: 1735 AN: 4818

European-Finnish (FIN) AF: 0.396 AC: 4178 AN: 10556

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.435 AC: 29508 AN: 67912

Other (OTH) AF: 0.410 AC: 863 AN: 2106

Alfa AF: 0.435 Hom.: 45272

Bravo AF: 0.455

Asia WGS AF: 0.281 AC: 980 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.29
DANN	Benign	0.50
PhyloP100		-0.098
Mutation Taster		=100/0	polymorphism (auto)

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: rs906216; hg19: chr10-71098195;