NM_000340.2:c.115_117del (p.Ile39del) is an in-frame deletion of a single amino acid in exon 3 of SLC2A2, encoding the GLUT2 glucose transporter. Loss-of-function variants in SLC2A2 cause Fanconi-Bickel syndrome (autosomal recessive) and have been implicated in neonatal diabetes.1 This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00284% (8/282,066 alleles, 0 homozygotes) and v4.1 allele frequency 0.00136% (22/1,612,532 alleles, 0 homozygotes). It is absent from gnomAD-Canada.2 The variant has been classified as Likely pathogenic in ClinVar (Variation ID: 631915) by two independent clinical testing laboratories, with Fulgent Genetics providing ACMG criteria with their submission.3 As an in-frame deletion in a non-repeat region, PM4 (supporting) applies. The variant does not qualify for PVS1, as it is not a null variant (nonsense, frameshift, or canonical splice site).4 No variant-specific literature was identified among the four ClinVar-linked PMIDs. PMID:25741868 (ACMG/AMP guidelines) and PMID:22962670 (hypertriglyceridemia guideline) were reviewed in full text; neither mentions NM_000340.2:c.115_117del or SLC2A2. PMID:20301750 (WFS1 Spectrum Disorder) and PMID:23492873 (EGAPP diabetes risk recommendations) are unrelated to this variant.
SLC2A2
Final classification
VUS
SLC2A2 c.115_117del · p.Ile39del
SLC2A2
NM_000340.2:c.115_117del (p.Ile39del) is an in-frame deletion of a single amino acid in exon 3 of SLC2A2, encoding the GLUT2 glucose transporter. Loss-of-function variants in SLC2A2 cause Fanconi-Bickel syndrome (autosomal recessive) and have been implicated in neonatal diabetes.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PM4 supporting, PP5 supporting; combination = 3 supporting, which maps to VUS.
Classification rationale
PM2PM4PP5
VUS
SLC2A2 c.115_117del
PM2 + PM4 + PP5
→
VUS
Gene diagram
· NM_000340.2 · variants mapped to exon structure
SLC2A2
NM_000340.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 18 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000340.2:c.115_117del is present at extremely low frequency in gnomAD: v2.1 allele frequency 0.00284% (8/282,066 alleles, 0 homozygotes) and v4.1 allele frequency 0.00136% (22/1,612,532 alleles, 0 homozygotes). Absent from gnomAD-Canada. The allele frequency is well below the 0.1% threshold for PM2.
gnomAD v2.1 AF = 0.0000284 (0.00284%)8/282066 alleles
✓
PM4
supporting
Pathogenic
NM_000340.2:c.115_117del (p.Ile39del) is an in-frame deletion of a single amino acid in exon 3 of SLC2A2, not located in a known repetitive region. In-frame deletions in non-repeat regions meet PM4 at supporting strength per ClinGen SVI guidance.
In-frame deletion of codon 39 (p.Ile39del) in exon 3/11 of SLC2A2Not in a repetitive region
✓
PP5
supporting
Pathogenic
Two clinical testing laboratories (PreventionGenetics and Fulgent Genetics) have classified NM_000340.2:c.115_117del as Likely pathogenic in ClinVar (Variation ID: 631915). Fulgent Genetics provided ACMG criteria with their submission (SCV005661889). While no expert panel classification exists, two independent clinical laboratories agree on a likely pathogenic classification, meeting PP5 at supporting level.
ClinVar Variation ID 631915: Likely pathogenic2 clinical laboratory submitters (PreventionGeneticsFulgent Genetics)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data were identified for this variant in ClinVar submissions or the reviewed literature.
PS3
One ClinVar submission (SCV004120392, PreventionGenetics) mentions functional studies suggesting impaired glucose uptake, but this submission has no assertion criteria, no validated PMIDs, and the cited study could not be verified.
PS4
Insufficient case-control or prevalence data to compare affected versus general population frequencies.
PM1
This variant does not lie in a statistically significant mutational hotspot (evidence_brief hotspots: not significant).
PM6
No de novo occurrence data (with or without confirmed paternity) were identified for this variant.
PP1
No cosegregation data were identified for this variant.
PP3
In silico prediction tools (REVEL, BayesDel) were not applicable to this non-SNV variant.
PP4
No patient phenotype or clinical data were available for this variant in the reviewed evidence.
Benign
BA1
The allele frequency in gnomAD v2.1 (0.00284%) and v4.1 (0.00136%) is far below the BA1 threshold of >1%.
BS1
The allele frequency in gnomAD v2.1 (0.00284%) and v4.1 (0.00136%) is far below the BS1 threshold of >0.3%.
BS2
No data on homozygous or hemizygous occurrence in healthy adults were identified.
BS3
No well-established functional studies showing no deleterious effect were identified for this variant.
BS4
No nonsegregation data were identified for this variant.
BP2
No data on observation in trans with a dominant pathogenic variant were identified.
BP3
BP3 applies to in-frame deletions in repetitive regions without known function.
BP4
SpliceAI predicts no splicing impact (max delta = 0.00), but REVEL and BayesDel are not applicable to non-SNV variants.
BP5
No data on this variant being found in a case with an alternate molecular basis for disease were identified.
BP6
BP6 requires a reputable source to classify the variant as benign.
N/A · 7
PVS1 · PS1 · PM3 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.36431e-05; MAF= 0.00136%, 22/1612532 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20349e-05; MAF= 0.00320%, 2/62432 alleles, homozygotes = 0); grpmax FAF= 8.79e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.83622e-05; MAF= 0.00284%, 8/282066 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.11688e-05; MAF= 0.00812%, 2/24640 alleles, homozygotes = 0); grpmax FAF= 1.124e-05.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00043426338074041906, 8/18422 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014%
· 22 / 1,612,532
0 hom · FAF 0.00088%
0 hom · FAF 0.00088%
Remaining individuals 2 / 62,432 |
0.0032% |
Admixed American 1 / 60,004 |
0.0017% |
European (Finnish) 1 / 64,026 |
0.0016% |
European (non-Finnish) 17 / 1,178,644 |
0.0014% |
African/African American 1 / 74,900 |
0.0013% |
+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0028%
· 8 / 282,066
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
African/African American 2 / 24,640 |
0.0081% |
European (Finnish) 1 / 25,116 |
0.004% |
European (non-Finnish) 5 / 128,812 |
0.0039% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
0.043%
· 8 / 18,422
0 hom · FAF 0.034%
0 hom · FAF 0.034%
European (non-Finnish) 8 / 11,742 |
0.068% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
22962670 ↗
Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.
CLINVAR
23492873 ↗
Recommendations from the EGAPP Working Group: does genomic profiling to assess type 2 diabetes risk improve health outcomes?
CLINVAR