rs74537742

Variant names:

• chr2-27094472-A-G
• rs74537742
• NM_006488.3:c.210-328A>G

Variant summary

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

The NM_000221.3(KHK):​c.210-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,613,080 control chromosomes in the GnomAD database, including 1,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (833 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (688 hom.)
• Consequence: KHK NM_000221.3 splice_region, intron
• Scores: Splicing: ADA: 0.001299
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.35
• Publications: 2 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 (BayesDel_noAF=-0.49).
• BP6: Variant 2-27094472-A-G is Benign according to our data. Variant chr2-27094472-A-G is described in ClinVar as Benign. ClinVar VariationId is 335485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000221.3. 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.210-328A>G		intron	N/A	NP_006479.1	P50053-1
	KHK	NM_000221.3		c.210-5A>G		splice_region intron	N/A	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.210-328A>G		intron	N/A	ENSP00000260598.5	P50053-1
	KHK	ENST00000260599.11	TSL:1	c.210-5A>G		splice_region intron	N/A	ENSP00000260599.6	P50053-2
	KHK	ENST00000908283.1		c.319A>G	p.Ser107Gly	missense	Exon 3 of 9	ENSP00000578342.1

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8677 AN: 151952 Hom.: 828 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0455

GnomAD2 exomes AF: 0.0145 AC: 3645 AN: 251086 AF XY: 0.0103

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00563 AC: 8223 AN: 1461010 Hom.: 688 Cov.: 32 AF XY: 0.00476 AC XY: 3458 AN XY: 726832

African (AFR) AF: 0.199 AC: 6667 AN: 33460

American (AMR) AF: 0.0110 AC: 494 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.0110 AC: 58 AN: 5262

European-Non Finnish (NFE) AF: 0.000164 AC: 182 AN: 1112008

Other (OTH) AF: 0.0127 AC: 767 AN: 60320

GnomAD4 genome AF: 0.0573 AC: 8712 AN: 152070 Hom.: 833 Cov.: 33 AF XY: 0.0545 AC XY: 4052 AN XY: 74322

African (AFR) AF: 0.199 AC: 8236 AN: 41444

American (AMR) AF: 0.0221 AC: 338 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67998

Other (OTH) AF: 0.0450 AC: 95 AN: 2112

Alfa AF: 0.0274 Hom.: 230

Bravo AF: 0.0658

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000178

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
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.84
PhyloP100		2.4
Mutation Taster		=37/63	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
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: rs74537742; hg19: chr2-27317340;