PVS1 is not applicable. NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln), not a null variant meeting ClinGen SVI PVS1 criteria.1 PM2 (Supporting) is met. The variant is present in gnomAD at extremely low frequency — v2.1 AF 2.13e-05 (6/282,168 alleles), v4.1 AF 1.99e-05 (32/1,611,868 alleles), grpmax FAF 1.13e-05 to 8.17e-05 — well below the 0.1% threshold. Absent from gnomAD-Canada. Zero homozygotes observed.2 PP3 (Supporting) is met. Multiple computational predictors support a deleterious effect: REVEL score 0.84 (strongly pathogenic range, >0.5), BayesDel no-AF score 0.352 (above deleterious threshold >0.27). SpliceAI predicts no splicing impact (delta 0.0), consistent with a coding missense variant.3 No pathogenic criteria beyond PM2 and PP3 (both supporting) are met. No benign criteria are met. All moderate, strong, and very strong criteria are either not applicable, not assessed, or not met. Per ACMG/AMP 2015 combination rules (PMID:25741868), two supporting pathogenic criteria (PM2_Supporting + PP3_Supporting) are insufficient to reach Likely Pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).4
SLC2A2
Final classification
VUS
SLC2A2 c.1094G>A · p.Arg365Gln
SLC2A2
PVS1 is not applicable. NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln), not a null variant meeting ClinGen SVI PVS1 criteria.
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, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
SLC2A2 c.1094G>A
PM2 + PP3
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_000340.2 · variants mapped to exon structure
SLC2A2
NM_000340.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000340.2:c.1094G>A is present in gnomAD at extremely low allele frequency: v2.1 AF 2.13e-05 (6/282,168 alleles, grpmax FAF 1.13e-05) and v4.1 AF 1.99e-05 (32/1,611,868 alleles, grpmax FAF 8.17e-05), well below the 0.1% PM2 threshold. No homozygotes observed. This is an autosomal recessive disorder (Fanconi-Bickel syndrome), and very low population frequency is consistent with pathogenicity.
gnomAD v2.1 total AF 2.13e-05 (6/282168)v4.1 total AF 1.99e-05 (32/1
✓
PP3
supporting
Pathogenic
Multiple lines of computational evidence support a deleterious effect. REVEL score of 0.84 is strongly predictive of pathogenicity (threshold >0.5). BayesDel no-AF score of 0.352 is above the deleterious threshold of 0.27. SpliceAI predicts no splicing impact (max delta = 0.0), which is expected for a coding missense variant and does not negate the REVEL and BayesDel predictions.
REVEL 0.84 (deleterious)BayesDel 0.352 (deleterious)SpliceAI max delta 0.0 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 365 producing the same amino acid substitution (p.Arg365Gln) classified as pathogenic was identified.
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional studies were identified for NM_000340.2:c.1094G>A (p.Arg365Gln).
PS4
No case-control or statistical enrichment data are available.
PM1
Residue Arg365 does not lie in a statistically significant mutational hotspot per CancerHotspots.org.
PM6
No de novo data are available.
PP1
No cosegregation data are available.
PP2
No gene-level constraint metrics (e.g., missense Z-score, gnomAD o/e) are available for SLC2A2 to determine whether the gene has a low rate of benign missense variation.
PP4
No patient phenotype or clinical data are available for the individual(s) carrying this variant.
PP5
PP5 requires a reputable source to have reported the variant as pathogenic with evidence unavailable for independent evaluation.
Benign
BA1
BA1 requires allele frequency >1% in population databases.
BS1
BS1 requires allele frequency >0.3% in population databases.
BS2
For recessive disorders, BS2 requires observation of the variant in homozygous state in healthy adults.
BS3
No well-established functional studies demonstrating no deleterious effect of p.Arg365Gln on GLUT2 protein function were identified.
BS4
No segregation data are available to assess lack of segregation with disease.
BP1
BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease.
BP2
No data available on observation in trans with a pathogenic variant (for dominant disorders) or in cis with a pathogenic variant.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact.
BP5
No data available on the variant being found in a case with an alternative molecular basis for disease.
BP6
BP6 requires a reputable source to report the variant as benign.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.98527e-05; MAF= 0.00199%, 32/1611868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000147043; MAF= 0.01470%, 11/74808 alleles, homozygotes = 0); grpmax FAF= 8.165e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.12639e-05; MAF= 0.00213%, 6/282168 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00609e-05; MAF= 0.00401%, 1/24962 alleles, homozygotes = 0); grpmax FAF= 1.125e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.002%
· 32 / 1,611,868
0 hom · FAF 0.0082%
0 hom · FAF 0.0082%
African/African American 11 / 74,808 |
0.015% |
Admixed American 3 / 59,886 |
0.005% |
European (non-Finnish) 18 / 1,178,350 |
0.0015% |
+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0021%
· 6 / 282,168
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
African/African American 1 / 24,962 |
0.004% |
European (non-Finnish) 5 / 128,674 |
0.0039% |
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.84. BayesDel score = 0.351945.
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 previously been reported in somatic cancers (COSMIC; COSV100049434, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links