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SPG11
Final classification
VUS
SPG11 c.6062G>A · p.Arg2021Gln
SPG11

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

Gene
SPG11
Transcript
NM_025137.4
HGVS · transcript:coding
NM_025137.4:c.6062G>A
Consequence
N/A
GRCh38
chr15:44573690 C>T
GRCh37
chr15:44865888 C>T
Basis 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; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting. ▾
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; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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 ↗
Gene diagram · NM_025137.4 · variants mapped to exon structure
SPG11 NM_025137.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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 screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).
      ClinVar ↗
      SpliceAI screenshot
      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 screenshot
      COSMIC
      Cancer hotspots screenshot
      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