About SLC2A2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SLC2A2 c.1094G>A, p.(Arg365Gln)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
32 / 1,611,868 alleles
gnomAD v4.1: 32 / 1,611,868 alleles. Recorded AF 1.98527e-05. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV100049434, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 8 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 2
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 2.13e-05 (6/282
- 168)
- v4.1 total AF 1.99e-05 (32/1
- 611
- 868). grpmax FAF 1.13e-05 (v2.1) to 8.17e-05 (v4.1). Absent from gnomAD-Canada. All below 0.1% threshold.
Sources
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.84 (deleterious)
- BayesDel 0.352 (deleterious)
- SpliceAI max delta 0.0 (no splice impact).
Still missing
- HCI prior not available for SLC2A2.
Sources
Not met · 8 · evaluated, threshold not reached
PM1 Residue Arg365 does not lie in a statistically significant mutational hotspot per CancerHotspots.org. No functional domain annotation from OncoKB is available to support localization to a critical domain. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot
- no OncoKB functional domain classification available.
Still missing
- No domain-level functional annotation from OncoKB
- no GLUT2 domain mapping.
Sources
PP5 PP5 requires a reputable source to have reported the variant as pathogenic with evidence unavailable for independent evaluation. NM_000340.2:c.1094G>A is absent from ClinVar; no reputable source has classified this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available.
Sources
BA1 BA1 requires allele frequency >1% in population databases. The highest observed population frequency is 0.015% (gnomAD v4.1 African/African American), far below the 1% threshold. Details ▾Hide ▴
Evidence considered
- Maximum population AF 0.0147% (gnomAD v4.1
- African/African American)
- total AF ~0.002%. Well below BA1 1% threshold.
Sources
BS1 BS1 requires allele frequency >0.3% in population databases. The variant frequency (~0.002%) is far below this threshold. Details ▾Hide ▴
BS2 For recessive disorders, BS2 requires observation of the variant in homozygous state in healthy adults. No homozygotes are observed in gnomAD (0 homozygotes across v2.1 and v4.1 combined). BS2 is not met. Details ▾Hide ▴
Evidence considered
- 0 homozygotes observed across gnomAD v2.1 and v4.1
- does not satisfy BS2 for a recessive disorder.
Sources
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. SLC2A2 is associated with Fanconi-Bickel syndrome and neonatal diabetes, with both missense and truncating variants reported as disease-causing. Published SLC2A2 disease cohorts include missense variants as pathogenic. Details ▾Hide ▴
Evidence considered
- SLC2A2 disease mechanism includes both missense and truncating pathogenic variants
- BP1 condition not satisfied.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. REVEL score of 0.84 strongly supports a deleterious effect, directly conflicting with BP4. While SpliceAI shows no splice impact (delta = 0.0) and BayesDel is intermediate (0.352), the strong REVEL prediction precludes BP4 application. Details ▾Hide ▴
Evidence considered
- REVEL 0.84 predicts deleterious effect
- conflicts with BP4. Computational evidence does not support a benign interpretation.
Sources
BP6 BP6 requires a reputable source to report the variant as benign. The variant is absent from ClinVar and no reputable source has classified it as benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classifies it as benign.
Sources
Not assessed · 12 · no assessment recorded
PS1 No evidence of a different nucleotide change at codon 365 producing the same amino acid substitution (p.Arg365Gln) classified as pathogenic was identified. No ClinVar records exist for this variant or same-residue comparators. Details ▾Hide ▴
Evidence considered
- No same-amino-acid pathogenic comparator variants identified in ClinVar or literature.
Still missing
- No ClinVar or published evidence for an alternate nucleotide change at Arg365 producing Arg365Gln.
PS2 No de novo data are available for this variant. No publications or database records report a de novo occurrence of NM_000340.2:c.1094G>A. Details ▾Hide ▴
Evidence considered
- No de novo observations identified.
Still missing
- No parental testing or de novo reports available.
PS3 No variant-specific functional studies were identified for NM_000340.2:c.1094G>A (p.Arg365Gln). REVEL and BayesDel are in silico predictors, not well-established functional assays. COSMIC reports one somatic occurrence (COSV100049434) which does not constitute germline functional evidence. Details ▾Hide ▴
Evidence considered
- No published functional studies identified. In silico predictors (REVEL
- BayesDel) are assessed separately under PP3/BP4.
Still missing
- No in vitro or in vivo functional characterization of p.Arg365Gln.
PS4 No case-control or statistical enrichment data are available. The variant is absent from ClinVar and no published case series specifically reporting this variant were identified. Details ▾Hide ▴
Evidence considered
- No case-control or enrichment data available.
Still missing
- No case-control studies or statistical enrichment analyses available.
PM6 No de novo data are available. PM6 requires a confirmed de novo occurrence with confirmed maternity and paternity. No such reports were identified for NM_000340.2:c.1094G>A. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo testing data available.
PP1 No cosegregation data are available. No family studies reporting segregation of NM_000340.2:c.1094G>A with Fanconi-Bickel syndrome or other SLC2A2-related phenotypes were identified. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
Still missing
- No family-based segregation studies 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. PP2 cannot be applied without these data. Details ▾Hide ▴
Evidence considered
- No constraint metrics (missense Z-score
- o/e ratio) available for SLC2A2.
Still missing
- SLC2A2 missense constraint metrics not available in current evidence.
PP4 No patient phenotype or clinical data are available for the individual(s) carrying this variant. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available.
Still missing
- No patient phenotype or clinical data provided.
BS3 No well-established functional studies demonstrating no deleterious effect of p.Arg365Gln on GLUT2 protein function were identified. Details ▾Hide ▴
Evidence considered
- No benign functional evidence available.
Still missing
- No functional studies evaluating p.Arg365Gln.
BS4 No segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family-based segregation data.
BP2 No data available on observation in trans with a pathogenic variant (for dominant disorders) or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No phase information available.
Still missing
- No phasing data with other pathogenic variants.
BP5 No data available on the variant being found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternative molecular basis data available.
Still missing
- No data on alternate molecular diagnoses in carriers.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln) and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant. PVS1 gene-level gate is eligible (SLC2A2 loss of function is an established germline disease mechanism for Fanconi-Bickel syndrome)
- but the variant type precludes PVS1 application per ClinGen SVI framework (PMC6185798).
Sources
PM5 N/APM5 requires a different pathogenic missense change at the same residue. No same-residue comparator variants (at Arg365) classified as pathogenic were identified in ClinVar. PM5 candidate harvesting was unable to confirm classic same-residue semantics. Details ▾Hide ▴
Evidence considered
- No pathogenic same-residue comparator variants at Arg365 identified.
Sources
pm5_candidates
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
PS5 N/APS5 is not a criterion in the ACMG/AMP 2015 framework; it was removed from the classification rubric. Details ▾Hide ▴
Evidence considered
- Criterion does not exist in the governing framework (generic_acmg / ACMG/AMP 2015).
Identifiers
- Gene
- SLC2A2
- Transcript
- NM_000340.2
- Coding (HGVS c.)
- NM_000340.2:c.1094G>A
- Protein (HGVS p.)
- NP_000331.1:p.(Arg365Gln)
- GRCh38
- chr3:170999141 C>T
- GRCh37
- chr3:170716930 C>T
- COSMIC
- COSV100049434
Gene diagram
Every interpreted variant in SLC2A2, mapped onto the exon structure of NM_000340.2. Select a row to find it on the plot.
SLC2A2NM_000340.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SLC2A2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
32 / 1,611,868 alleles
AF 1.99e-05 · 0 homozygotes · FAF 8.16e-05
gnomAD v2.1
6 / 282,168 alleles
AF 2.13e-05 · 0 homozygotes · FAF 1.13e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2e-05 · 32 / 1,611,868 alleles · 0 hom · FAF 8.2e-05
| African/African American11 / 74,808 | 0.00015 |
| Admixed American3 / 59,886 | 5e-05 |
| European (non-Finnish)18 / 1,178,350 | 1.5e-05 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 2.1e-05 · 6 / 282,168 alleles · 0 hom · FAF 1.1e-05
| African/African American1 / 24,962 | 4e-05 |
| European (non-Finnish)5 / 128,674 | 3.9e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.840
- BayesDel
- 0.352
How the predictions were used
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.84 (deleterious)
- BayesDel 0.352 (deleterious)
- SpliceAI max delta 0.0 (no splice impact).
Still missing
- HCI prior not available for SLC2A2.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. REVEL score of 0.84 strongly supports a deleterious effect, directly conflicting with BP4. While SpliceAI shows no splice impact (delta = 0.0) and BayesDel is intermediate (0.352), the strong REVEL prediction precludes BP4 application. Details ▾Hide ▴
Evidence considered
- REVEL 0.84 predicts deleterious effect
- conflicts with BP4. Computational evidence does not support a benign interpretation.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.84. BayesDel score = 0.351945.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
32 / 1,611,868 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000340.2%3Ac.1094G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-170716930-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-170999141-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-170999141-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000340.2%3Ac.1094…
- OncoKB ↗www.oncokb.org/gene/SLC2A2/R365Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=125367812
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.84. BayesDel score = 0.351945.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100049434, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.