2-27099732-C-A

Variant names:

• chr2-27099732-C-A
• rs116026105
• NM_006488.3:c.879C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006488.3(KHK):​c.879C>A​(p.Gly293Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,114 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (13 hom.)
• Consequence: KHK NM_006488.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.392
• Publications: 0 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]

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-27099732-C-A is Benign according to our data. Variant chr2-27099732-C-A is described in ClinVar as Benign. ClinVar VariationId is 711815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00676 (1029/152266) while in subpopulation AFR AF = 0.0236 (980/41564). AF 95% confidence interval is 0.0224. There are 11 homozygotes in GnomAd4. There are 494 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.879C>A	p.Gly293Gly	synonymous	Exon 8 of 8	NP_006479.1	P50053-1
	KHK	NM_000221.3		c.879C>A	p.Gly293Gly	synonymous	Exon 8 of 8	NP_000212.1	P50053-2
	CGREF1	NM_001166240.2		c.*52G>T		3_prime_UTR	Exon 6 of 6	NP_001159712.1	Q99674-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KHK	ENST00000260598.10	TSL:2 MANE Select	c.879C>A	p.Gly293Gly	synonymous	Exon 8 of 8	ENSP00000260598.5	P50053-1
	KHK	ENST00000260599.11	TSL:1	c.879C>A	p.Gly293Gly	synonymous	Exon 8 of 8	ENSP00000260599.6	P50053-2
	KHK	ENST00000464371.1	TSL:1	n.805C>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1026 AN: 152148 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00164 AC: 408 AN: 249064 AF XY: 0.00110

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000738 AC: 1079 AN: 1461848 Hom.: 13 Cov.: 33 AF XY: 0.000670 AC XY: 487 AN XY: 727224

African (AFR) AF: 0.0249 AC: 834 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1111994

Other (OTH) AF: 0.00176 AC: 106 AN: 60394

GnomAD4 genome AF: 0.00676 AC: 1029 AN: 152266 Hom.: 11 Cov.: 32 AF XY: 0.00664 AC XY: 494 AN XY: 74452

African (AFR) AF: 0.0236 AC: 980 AN: 41564

American (AMR) AF: 0.00209 AC: 32 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00231 Hom.: 5

Bravo AF: 0.00755

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Essential fructosuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism

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: rs116026105; hg19: chr2-27322600;