Classification rationale

PM2 BP4 VUS

SPG11 c.6062G>A

The SPG11 c.6062G>A (p.Arg2021Gln) variant has been reported in ClinVar with one likely benign submission and one uncertain significance submission.¹ This variant is rare in population databases, with the highest observed frequency in East Asian individuals of 0.09023% in gnomAD v2.1 and 0.05125% in gnomAD v4.1, both below the 0.1% PM2 threshold used for this generic non-VCEP review.² Computational data argue against a damaging effect, with REVEL 0.113, BayesDel -0.445237, and SpliceAI showing no significant predicted splice impact with a maximum delta score of 0.02.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

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.

Gene diagram · NM_025137.4 · variants mapped to exon structure

SPG11 NM_025137.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 moderate Pathogenic

This variant is rare in population databases. In gnomAD v2.1, the highest observed population frequency was 0.09023% in East Asian individuals, and in gnomAD v4.1 it was 0.05125% in East Asian individuals; both are below the 0.1% PM2 threshold used for this generic non-VCEP review.

gnomAD v2.1 East Asian AF 0.000902346 (18/19948)gnomAD v4.1 East Asian AF 0.000512501 (23/44878)Both below 0.001

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Multiple computational results support a benign interpretation. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, which together argue against a damaging protein or splice effect.

REVEL 0.113 supports a benign missense interpretationBayesDel -0.445237 supports a benign interpretationSpliceAI max delta 0.02 argues against splice disruption

spliceai ↗

Assessed · not applied · 6 not met · 14 not assessed

Pathogenic

PS1 No evidence was identified showing that a different nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic, so PS1 was not assessed.

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not assessed.

PS3 No well-established functional studies were identified showing a damaging effect of p.(Arg2021Gln), so PS3 was not assessed.

PS4 Available evidence does not show enrichment of this variant in affected individuals compared with controls.

PM1 This variant has not been shown to lie in a well-established critical functional domain or statistically significant mutational hotspot.

PM3 No case-level evidence was identified showing this variant in trans with a pathogenic or likely pathogenic SPG11 variant in an affected individual, so PM3 was not assessed.

PM5 No evidence was identified showing a different pathogenic missense change at codon 2021, so PM5 was not assessed.

PM6 No presumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP2 Available evidence was insufficient to show that SPG11 is a gene in which missense variation is a common disease mechanism and benign missense variation is uncommon, so PP2 was not assessed.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype-specific clinical data were available to determine whether the observed presentation is highly specific for SPG11-related disease, so PP4 was not assessed.

Benign

BA1 The population frequency is well below the 1% BA1 threshold.

BS1 The population frequency is below the 0.3% BS1 threshold used for this generic non-VCEP review.

BS2 This variant was not observed in homozygous state in the reviewed population data, and no evidence was identified showing the full disease-relevant genotype in healthy individuals, so BS2 was not met.

BS3 No well-established functional studies were identified showing normal function for p.(Arg2021Gln), so BS3 was not assessed.

BS4 No non-segregation data were identified for this variant, so BS4 was not assessed.

BP1 SPG11 loss of function is a known disease mechanism, but the available evidence was insufficient to conclude that missense variants are generally not disease-causing in this gene, so BP1 was not assessed.

BP2 No phase information was identified showing this variant in cis with a pathogenic variant or in trans in a context supporting BP2, so BP2 was not assessed.

BP5 No evidence was identified for an alternate molecular explanation for the phenotype independent of this variant, so BP5 was not assessed.

N/A · 6 PVS1 · PM4 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.70831e-05; MAF= 0.00471%, 76/1614168 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000512501; MAF= 0.05125%, 23/44878 alleles, homozygotes = 0); grpmax FAF= 0.00034976.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.84242e-05; MAF= 0.00884%, 25/282728 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000902346; MAF= 0.09023%, 18/19948 alleles, homozygotes = 0); grpmax FAF= 0.00058897.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0047% · 76 / 1,614,168
0 hom · FAF 0.035%

East Asian 23 / 44,878	0.051%
Middle Eastern 1 / 6,062	0.016%
Admixed American 8 / 60,016	0.013%
Remaining individuals 8 / 62,510	0.013%
South Asian 9 / 91,084	0.0099%
European (non-Finnish) 26 / 1,180,038	0.0022%
African/African American 1 / 75,032	0.0013%

+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.0088% · 25 / 282,728
0 hom · FAF 0.059%

East Asian 18 / 19,948	0.09%
Remaining individuals 1 / 7,218	0.014%
Admixed American 4 / 35,428	0.011%
European (non-Finnish) 2 / 129,072	0.0015%

+ 4 not observed (African/African American, Ashkenazi Jewish, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.113. BayesDel score = -0.445237.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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