NM_020821.3:c.5566G>T

VPS13C · NP_065872.1:p.(Gly1856Trp) · NM_020821.3

GRCh37: chr15:62232881 C>A · GRCh38: chr15:61940682 C>A

Gene: VPS13C Transcript: NM_020821.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

VPS13C

Transcript

NM_020821.3

Protein

NP_065872.1:p.(Gly1856Trp)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental testing was identified, so PS2 was not assessed.	clinvar
PS3	Not assessed	No well-established functional study for this exact variant was identified, so PS3 was not assessed.
PS4	Not assessed	No enrichment data or repeated observations in affected individuals were identified for this variant, so PS4 was not assessed.	clinvar
PM1	Not assessed	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.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	No observations of this variant in trans with a pathogenic or likely pathogenic variant were identified, so PM3 was not assessed.	clinvar
PM4	N/A	This variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable.
PM5	Not assessed	No different pathogenic missense change at codon 1856 was identified from the available evidence, so PM5 was not assessed.	clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.
PP2	Not assessed	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.
PP3	Not met	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.	spliceai revel bayesdel
PP4	Not assessed	No phenotype information specific enough to establish a highly specific clinical presentation for this variant was identified, so PP4 was not assessed.
PP5	Not assessed	No reputable source classification for this exact variant was identified, so PP5 was not assessed.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a count sufficient for BS2, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing retained or normal function for this exact variant was identified, so BS3 was not assessed.
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP1	Not assessed	Available evidence did not establish that benign interpretation is favored because only truncating variants cause disease in this gene, so BP1 was not assessed.
BP2	Not assessed	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.	clinvar
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable.
BP4	Met	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.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation for the observed phenotype was provided, so BP5 was not assessed.
BP6	Not assessed	No reputable source benign classification for this exact variant was identified, so BP6 was not assessed.	clinvar
BP7	N/A	This variant is missense rather than synonymous or intronic, so BP7 is not applicable.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.