Starting
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CUX1
Final classification
VUS
CUX1 c.1227G>A · p.Ala409=
CUX1

The CUX1 NM_001202543.1:c.1227G>A (NP_001189472.1:p.(Ala409=)) variant has not been reported in ClinVar, and curated cancer review resources did not provide variant-specific oncogenic evidence.

Gene
CUX1
Transcript
NM_001202543.1
HGVS · transcript:coding
NM_001202543.1:c.1227G>A
Consequence
N/A
GRCh38
chr7:102195575 G>A
GRCh37
chr7:101838855 G>A
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 benign; combination = 1 moderate, 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 benign; combination = 1 moderate, which maps to VUS because the evidence is conflicting.
Classification rationale
PM2 BP4 VUS
CUX1 c.1227G>A

The CUX1 NM_001202543.1:c.1227G>A (NP_001189472.1:p.(Ala409=)) variant has not been reported in ClinVar, and curated cancer review resources did not provide variant-specific oncogenic evidence.1 This variant is very rare in population databases, with allele frequencies of 8.17e-06 (2/244722; 0.00082%) in gnomAD v2.1 and 8.07e-06 (13/1611678; 0.00081%) in gnomAD v4.1.2 CUX1 loss of function is an established germline disease mechanism, but this synonymous variant is not a generic PVS1-eligible loss-of-function variant.3 Computational splice prediction does not support a damaging effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.4

PM2 + BP4 → VUS
1 clinvar ↗oncokb ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
4 spliceai ↗
Gene diagram · NM_001202543.1 · variants mapped to exon structure
CUX1 NM_001202543.1
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= 8.06613e-06; MAF= 0.00081%, 13/1611678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.3344e-05; MAF= 0.00133%, 1/74940 alleles, homozygotes = 0); grpmax FAF= 5.43e-06.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 8.17254e-06; MAF= 0.00082%, 2/244722 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.36618e-05; MAF= 0.00637%, 1/15708 alleles, homozygotes = 0).
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00081% · 13 / 1,611,678
      0 hom · FAF 0.00054%
      African/African American
      1 / 74,940
      0.0013%
      European (non-Finnish)
      12 / 1,179,520
      0.001%
      + 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
      gnomAD v2.1
      0.00082% · 2 / 244,722
      0 hom
      African/African American
      1 / 15,708
      0.0064%
      European (non-Finnish)
      1 / 110,668
      0.0009%
      + 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
      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