rs874556

Positions:

• chr10-69232908-C-G
• chr10-69232908-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000354624.6(HKDC1):​c.371C>G​(p.Thr124Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. T124I) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: HKDC1 ENST00000354624.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

Genes affected

HKDC1 (HGNC:23302): (hexokinase domain containing 1) This gene encodes a member of the hexokinase protein family. The encoded protein is involved in glucose metabolism, and reduced expression may be associated with gestational diabetes mellitus. High expression of this gene may also be associated with poor prognosis in hepatocarcinoma. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1445196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HKDC1	NM_025130.4	c.371C>G	p.Thr124Arg	missense_variant	3/18	ENST00000354624.6	NP_079406.4
HKDC1	XM_011540195.3	c.371C>G	p.Thr124Arg	missense_variant	3/16		XP_011538497.1
HKDC1	XR_007061989.1	n.475C>G		non_coding_transcript_exon_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HKDC1	ENST00000354624.6	c.371C>G	p.Thr124Arg	missense_variant	3/18	1	NM_025130.4	ENSP00000346643	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 60

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.040	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.31
Sift	Benign	0.21	T
Sift4G	Benign	0.46	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.48		Gain of solvent accessibility (P = 0.0456);
MVP		0.67
MPC		0.18
ClinPred		0.073	T
GERP RS		1.7
Varity_R		0.26
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs874556; hg19: chr10-70992664;