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VPS13Cc.5566G>TUncertain significance
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Variant interpretation report

VPS13C c.5566G>T, p.(Gly1856Trp)

NM_020821.3:c.5566G>T NP_065872.1:p.(Gly1856Trp) View identifiers
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.

About VPS13C

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which places the allele frequency below the non-VCEP PM2 threshold of 0.1%, supporting rarity in population databases.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple computational results argue against a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.11, which is below 0.2, REVEL is 0.261, and BayesDel is -0.307905, together supporting BP4.

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 moderate, BP4 supporting benign; combination = 1 moderate, which maps to VUS because the evidence is conflicting.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
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
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 19 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The VPS13C c.5566G>T (p.Gly1856Trp; p.G1856W) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the 0.1% rarity threshold used for PM2.

Computational evidence does not support a damaging or splice-altering effect: SpliceAI predicts no significant splice impact with a max delta score of 0.11, REVEL is 0.261, and BayesDel is -0.307905.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which places the allele frequency below the non-VCEP PM2 threshold of 0.1%, supporting rarity in population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational results argue against a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.11, which is below 0.2, REVEL is 0.261, and BayesDel is -0.307905, together supporting BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.11
  • REVEL score 0.261
  • BayesDel score -0.307905
Sources
spliceai ↗revelbayesdel

Not met · 3 · evaluated, threshold not reached

PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.11, which is below 0.2, and the missense predictors are not strongly pathogenic (REVEL 0.261; BayesDel -0.307905), so PP3 is not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.11
  • REVEL score 0.261
  • BayesDel score -0.307905
Sources
spliceai ↗revelbayesdel
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the stand-alone benign frequency threshold of more than 1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the strong benign frequency threshold of more than 0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 19 · no assessment recorded

PS1 No evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic classification, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar does not contain this exact variant
Still missing
  • No same-amino-acid pathogenic comparison variant was identified.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with parental testing was identified, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar record or case-level parental data were identified
Still missing
  • No case report with confirmed maternity and paternity was identified.
Sources
clinvar ↗
PS3 No well-established functional study for this exact variant was identified, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • No PMID-backed functional evidence for p.Gly1856Trp was retrieved
Still missing
  • No variant-specific functional assay result was identified.
PS4 No enrichment data or repeated observations in affected individuals were identified for this variant, so PS4 was not assessed. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar
Still missing
  • No case-control data or multiple unrelated affected carriers were identified.
Sources
clinvar ↗
PM1 Available hotspot review did not identify a statistically significant hotspot at Gly1856, but the hotspot result was flagged for confirmation, so PM1 was not assessed. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review did not show a residue row for G1856
  • Hotspot interpretation was marked uncertain and needs human review
Still missing
  • No confirmed critical functional domain or mutational hotspot at codon 1856 was established.
Sources
hotspots ↗
PM3 No observations of this variant in trans with a pathogenic or likely pathogenic variant were identified, so PM3 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or case-level phase data were identified
Still missing
  • No phase-confirmed compound heterozygous or homozygous case data were identified for this exact variant.
Sources
clinvar ↗
PM5 No different pathogenic missense change at codon 1856 was identified from the available evidence, so PM5 was not assessed. Details ▾Hide ▴
Evidence considered
  • This exact variant is absent from ClinVar
Still missing
  • No established pathogenic missense comparator at the same codon was identified.
Sources
clinvar ↗
PM6 No assumed de novo occurrence without confirmed parentage was identified, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or case-level de novo note was identified
Still missing
  • No apparent de novo case report was identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
  • No segregation evidence was retrieved
Still missing
  • No family-based cosegregation data were identified.
PP2 Available evidence did not establish a gene-specific missense constraint or a predominance of pathogenic missense variation sufficient to apply PP2, so PP2 was not assessed. Details ▾Hide ▴
Evidence considered
  • No gene-specific PP2 rule was available
Still missing
  • No gene-level missense constraint framework was identified.
PP4 No phenotype information specific enough to establish a highly specific clinical presentation for this variant was identified, so PP4 was not assessed. Details ▾Hide ▴
Evidence considered
  • No phenotype packet was available for PP4
Still missing
  • No case-specific phenotype data were provided.
PP5 No reputable source classification for this exact variant was identified, so PP5 was not assessed. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar
Still missing
  • This variant is absent from ClinVar.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals at a count sufficient for BS2, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
  • This variant is absent from gnomAD v2.1 and gnomAD v4.1
Still missing
  • No control observations or adult homozygote data were identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study showing retained or normal function for this exact variant was identified, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • No variant-specific benign functional evidence was retrieved
Still missing
  • No benign functional assay result was identified.
BS4 No lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
  • No non-segregation evidence was retrieved
Still missing
  • No pedigree showing non-segregation was identified.
BP1 Available evidence did not establish that benign interpretation is favored because only truncating variants cause disease in this gene, so BP1 was not assessed. Details ▾Hide ▴
Evidence considered
  • No validated BP1 rule was available for VPS13C
Still missing
  • No gene-specific BP1 framework was identified.
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or phase data were identified
Still missing
  • No phase-resolved case data were identified.
Sources
clinvar ↗
BP5 No alternate molecular explanation for the observed phenotype was provided, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data were available
Still missing
  • No phenotype-level differential diagnosis information was provided.
BP6 No reputable source benign classification for this exact variant was identified, so BP6 was not assessed. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar
Still missing
  • This variant is absent from ClinVar.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.Gly1856Trp, and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • VPS13C loss of function is an eligible disease mechanism at the gene level
  • NM_020821.3:c.5566G>T is not in a default generic PVS1 null-variant bucket
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.Gly1856Trp
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is missense
  • not in-frame indel
BP7 N/AThis variant is missense rather than synonymous or intronic, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.Gly1856Trp

Identifiers

Gene
VPS13C
Transcript
NM_020821.3
Coding (HGVS c.)
NM_020821.3:c.5566G>T
Protein (HGVS p.)
NP_065872.1:p.(Gly1856Trp)
GRCh38
chr15:61940682 C>A
GRCh37
chr15:62232881 C>A

Gene diagram

Every interpreted variant in VPS13C, mapped onto the exon structure of NM_020821.3. Select a row to find it on the plot.

VPS13CNM_020821.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple computational results argue against a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.11, which is below 0.2, REVEL is 0.261, and BayesDel is -0.307905, together supporting BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.11
  • REVEL score 0.261
  • BayesDel score -0.307905
Sources
spliceai ↗revelbayesdel
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.11, which is below 0.2, and the missense predictors are not strongly pathogenic (REVEL 0.261; BayesDel -0.307905), so PP3 is not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.11
  • REVEL score 0.261
  • BayesDel score -0.307905
Sources
spliceai ↗revelbayesdel
BP7 N/AThis variant is missense rather than synonymous or intronic, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.Gly1856Trp

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.261. BayesDel score = -0.307905.

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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.261. BayesDel score = -0.307905.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.