chr2-27094472-A-G

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_006488.3(KHK):​c.210-328A>G variant causes a 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. 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_006488.3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHK	NM_006488.3	c.210-328A>G		intron_variant	Intron 2 of 7	ENST00000260598.10	NP_006479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHK	ENST00000260598.10	c.210-328A>G		intron_variant	Intron 2 of 7	2	NM_006488.3	ENSP00000260598.5

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Essential fructosuria Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;