Genetic Variant NM_025130.4:c.659A>G (chr10-69240719-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_025130.4(HKDC1):c.659A>G(p.Asp220Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HKDC1
NM_025130.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

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]

HKDC1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HKDC1	NM_025130.4 link	c.659A>G	p.Asp220Gly	missense_variant	Exon 6 of 18	ENST00000354624.6	NP_079406.4	Q2TB90-1B3KT70
HKDC1	XM_011540195.3 link	c.659A>G	p.Asp220Gly	missense_variant	Exon 6 of 16		XP_011538497.1
HKDC1	XM_047425784.1 link	c.83A>G	p.Asp28Gly	missense_variant	Exon 3 of 15		XP_047281740.1
HKDC1	XR_007061989.1 link	n.763A>G		non_coding_transcript_exon_variant	Exon 6 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HKDC1	ENST00000354624.6 link	c.659A>G	p.Asp220Gly	missense_variant	Exon 6 of 18	1	NM_025130.4	ENSP00000346643.5		Q2TB90-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.659A>G (p.D220G) alteration is located in exon 6 (coding exon 6) of the HKDC1 gene. This alteration results from a A to G substitution at nucleotide position 659, causing the aspartic acid (D) at amino acid position 220 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Benign

0.051

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.58

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.71

Sift

Benign

0.30

Sift4G

Benign

0.25

Polyphen

0.0010

Vest4

0.70

MutPred

0.53

Loss of phosphorylation at Y223 (P = 0.0905);

MVP

0.82

MPC

0.27

ClinPred

0.84

GERP RS

4.5

Varity_R

0.64

gMVP

0.73

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over