10-69232908-C-T

Variant names:

• chr10-69232908-C-T
• rs874556
• NM_025130.4:c.371C>T

Variant summary

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

The NM_025130.4(HKDC1):​c.371C>T​(p.Thr124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,612,120 control chromosomes in the GnomAD database, including 155,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (16966 hom., cov: 32)
  • Exomes 𝑓: 0.43 (138242 hom.)
• Consequence: HKDC1 NM_025130.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.1942857E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HKDC1	NM_025130.4	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 18	ENST00000354624.6	NP_079406.4
HKDC1	XM_011540195.3	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 16		XP_011538497.1
HKDC1	XR_007061989.1	n.475C>T		non_coding_transcript_exon_variant	Exon 3 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HKDC1	ENST00000354624.6	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 18	1	NM_025130.4	ENSP00000346643.5

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70789 AN: 151954 Hom.: 16935 Cov.: 32

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.455

GnomAD2 exomes AF: 0.464 AC: 115971 AN: 249776 AF XY: 0.458

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.465

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.428 AC: 625572 AN: 1460048 Hom.: 138242 Cov.: 60 AF XY: 0.428 AC XY: 310918 AN XY: 726442

African (AFR) AF: 0.544 AC: 18209 AN: 33478

American (AMR) AF: 0.461 AC: 20602 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 13002 AN: 26136

East Asian (EAS) AF: 0.797 AC: 31626 AN: 39700

South Asian (SAS) AF: 0.442 AC: 38090 AN: 86258

European-Finnish (FIN) AF: 0.454 AC: 23432 AN: 51638

Middle Eastern (MID) AF: 0.424 AC: 2443 AN: 5768

European-Non Finnish (NFE) AF: 0.406 AC: 450902 AN: 1111962

Other (OTH) AF: 0.452 AC: 27266 AN: 60384

GnomAD4 genome AF: 0.466 AC: 70871 AN: 152072 Hom.: 16966 Cov.: 32 AF XY: 0.472 AC XY: 35073 AN XY: 74342

African (AFR) AF: 0.540 AC: 22380 AN: 41472

American (AMR) AF: 0.417 AC: 6362 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1765 AN: 3470

East Asian (EAS) AF: 0.758 AC: 3923 AN: 5174

South Asian (SAS) AF: 0.460 AC: 2218 AN: 4820

European-Finnish (FIN) AF: 0.459 AC: 4855 AN: 10572

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27917 AN: 67976

Other (OTH) AF: 0.462 AC: 978 AN: 2116

Alfa AF: 0.422 Hom.: 42224

Bravo AF: 0.468

TwinsUK AF: 0.421 AC: 1562

ALSPAC AF: 0.412 AC: 1587

ESP6500AA AF: 0.529 AC: 2330

ESP6500EA AF: 0.415 AC: 3568

ExAC AF: 0.464 AC: 56379

Asia WGS AF: 0.615 AC: 2136 AN: 3478

EpiCase AF: 0.405

EpiControl AF: 0.403

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.017	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.15
ClinPred		0.0079	T
GERP RS		1.7
Varity_R		0.12
gMVP		0.43
Mutation Taster		=97/3	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: rs874556; hg19: chr10-70992664; COSMIC: COSV63575832; COSMIC: COSV63575832;