2-27092384-G-A

Variant names:

• chr2-27092384-G-A
• rs2304681
• NM_006488.3:c.145G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006488.3(KHK):​c.145G>A​(p.Val49Ile) variant causes a missense change. The variant allele was found at a frequency of 0.369 in 1,613,034 control chromosomes in the GnomAD database, including 113,460 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10529 hom., cov: 34)
  • Exomes 𝑓: 0.37 (102931 hom.)
• Consequence: KHK NM_006488.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.25
• Publications: 44 publications found

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]

KHK Gene-Disease associations (from GenCC):

• essential fructosuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3898482E-4).
• BP6: Variant 2-27092384-G-A is Benign according to our data. Variant chr2-27092384-G-A is described in ClinVar as Benign. ClinVar VariationId is 335482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006488.3. 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
	KHK	NM_006488.3	MANE Select	c.145G>A	p.Val49Ile	missense	Exon 2 of 8	NP_006479.1	P50053-1
	KHK	NM_000221.3		c.145G>A	p.Val49Ile	missense	Exon 2 of 8	NP_000212.1	P50053-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KHK	ENST00000260598.10	TSL:2 MANE Select	c.145G>A	p.Val49Ile	missense	Exon 2 of 8	ENSP00000260598.5	P50053-1
	KHK	ENST00000260599.11	TSL:1	c.145G>A	p.Val49Ile	missense	Exon 2 of 8	ENSP00000260599.6	P50053-2
	KHK	ENST00000908283.1		c.145G>A	p.Val49Ile	missense	Exon 2 of 9	ENSP00000578342.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55547 AN: 152056 Hom.: 10514 Cov.: 34

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.371

GnomAD2 exomes AF: 0.386 AC: 96856 AN: 250738 AF XY: 0.377

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.624

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.234

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.370 AC: 540369 AN: 1460860 Hom.: 102931 Cov.: 45 AF XY: 0.368 AC XY: 267576 AN XY: 726820

African (AFR) AF: 0.323 AC: 10797 AN: 33472

American (AMR) AF: 0.609 AC: 27210 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 10353 AN: 26134

East Asian (EAS) AF: 0.218 AC: 8664 AN: 39700

South Asian (SAS) AF: 0.313 AC: 26969 AN: 86244

European-Finnish (FIN) AF: 0.334 AC: 17627 AN: 52712

Middle Eastern (MID) AF: 0.354 AC: 2042 AN: 5768

European-Non Finnish (NFE) AF: 0.373 AC: 414956 AN: 1111732

Other (OTH) AF: 0.360 AC: 21751 AN: 60386

GnomAD4 genome AF: 0.365 AC: 55581 AN: 152174 Hom.: 10529 Cov.: 34 AF XY: 0.365 AC XY: 27182 AN XY: 74386

African (AFR) AF: 0.318 AC: 13215 AN: 41540

American (AMR) AF: 0.510 AC: 7799 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1374 AN: 3472

East Asian (EAS) AF: 0.240 AC: 1239 AN: 5158

South Asian (SAS) AF: 0.305 AC: 1473 AN: 4822

European-Finnish (FIN) AF: 0.327 AC: 3459 AN: 10594

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25652 AN: 67976

Other (OTH) AF: 0.374 AC: 791 AN: 2114

Alfa AF: 0.382 Hom.: 32268

Bravo AF: 0.383

TwinsUK AF: 0.357 AC: 1322

ALSPAC AF: 0.382 AC: 1472

ESP6500AA AF: 0.318 AC: 1399

ESP6500EA AF: 0.376 AC: 3231

ExAC AF: 0.377 AC: 45711

Asia WGS AF: 0.305 AC: 1061 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.384

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Essential fructosuria (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.25
Sift	Benign	0.065	T
Sift4G	Benign	0.078	T
Polyphen		0.52	P
Vest4		0.091
MPC		0.27
ClinPred		0.017	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.36
Mutation Taster		=99/1	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: rs2304681; hg19: chr2-27315252; COSMIC: COSV53153334; COSMIC: COSV53153334;