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LYFE SCIENCES
Project: HERA
NM_025137.4:c.6062G>A
p.Arg2021Gln  ·  SPG11
ACMG/AMP
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Legacy Engine
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Classification rationale
1

The SPG11 c.6062G>A (p.Arg2021Gln) variant has been reported in ClinVar with one likely benign submission and one uncertain significance submission.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).
ClinVar ↗
03
Functional
No functional summary recorded.
OncoKB ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR2021
Hotspots ↗