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 ↗

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_001202543.1 · variants mapped to exon structure

CUX1 NM_001202543.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 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 very rare in population databases, with gnomAD v2.1 AF 8.17e-06 (0.00082%; 2/244722) and gnomAD v4.1 AF 8.07e-06 (0.00081%; 13/1611678), both well below the 0.1% PM2 threshold.

gnomAD v2.1 total AF 8.17254e-06gnomAD v4.1 total AF 8.06613e-06

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Available computational evidence supports no impact on splicing: SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, and no damaging computational evidence was identified for this synonymous variant.

SpliceAI max delta score 0.00Synonymous consequence p.(Ala409=)

spliceai ↗

Assessed · not applied · 8 not met · 11 not assessed

Pathogenic

PVS1 CUX1 loss of function is an established germline disease mechanism, but this variant is a synonymous change, is not in a canonical +/-1,2 splice position, and does not fall into the generic PVS1 null-variant categories; available evidence does not support applying PVS1.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional study was identified for this exact variant.

PS4 No case enrichment, case-control, or multiple affected-individual observations were identified for this variant.

PM1 Available data do not place this variant in a well-established critical functional domain or statistically significant hotspot; Cancer Hotspots did not identify a significant hotspot at Ala409.

PM6 No presumed de novo occurrence was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and no additional damaging REVEL, BayesDel, or HCI prior evidence was identified.

PP4 No phenotype information was provided that is sufficiently specific to assess PP4 for this variant.

PP5 No reputable external classification source identifying this variant as pathogenic was found; the variant is absent from ClinVar.

Benign

BA1 Population frequency does not meet the BA1 threshold: the highest observed overall allele frequency is 8.07e-06 (0.00081%) in gnomAD v4.1, which is far below the 1% BA1 threshold.

BS1 Population frequency does not meet the BS1 threshold: the highest observed population frequency is 1.33e-05 (0.00133%) in gnomAD v4.1 African/African American samples, which is below the 0.3% BS1 threshold.

BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency or zygosity sufficient to support BS2.

BS3 No well-established functional study was identified showing no damaging effect for this exact variant.

BS4 No family data were identified showing lack of segregation with disease.

BP2 No phase data were identified to assess BP2.

BP5 No alternate molecular explanation was identified that would allow assessment of BP5.

BP6 No reputable external classification source identifying this variant as benign was found; the variant is absent from ClinVar.

BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but no conservation evidence was identified to complete BP7 assessment.

N/A · 7 PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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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