chr2-27099503-C-G

Variant names:

• chr2-27099503-C-G
• NM_006488.3:c.737C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006488.3(KHK):​c.737C>G​(p.Pro246Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P246L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KHK NM_006488.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.60

Genes affected

KHK (HGNC:6315): (ketohexokinase) This gene encodes ketohexokinase that catalyzes conversion of fructose to fructose-1-phosphate. The product of this gene is the first enzyme with a specialized pathway that catabolizes dietary fructose. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

CGREF1 (HGNC:16962): (cell growth regulator with EF-hand domain 1) Predicted to enable calcium ion binding activity. Predicted to be involved in negative regulation of cell population proliferation. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHK	NM_006488.3	c.737C>G	p.Pro246Arg	missense_variant	Exon 7 of 8	ENST00000260598.10	NP_006479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHK	ENST00000260598.10	c.737C>G	p.Pro246Arg	missense_variant	Exon 7 of 8	2	NM_006488.3	ENSP00000260598.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.98	D;D
Vest4		0.71
MutPred		0.61		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.81
MPC		0.72
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.61

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.

Other links and lift over

hg19: chr2-27322371;