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CUX1c.1227G>AUncertain significance
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Variant interpretation report

CUX1 c.1227G>A, p.(Ala409=)

NM_001202543.1:c.1227G>A NP_001189472.1:p.(Ala409=) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CUX1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
13 / 1,611,678 alleles

gnomAD v4.1: 13 / 1,611,678 alleles. Recorded AF 8.06613e-06. Recorded homozygote count 0.

gnomAD 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).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 8 not met · 11 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

CUX1 loss of function is an established germline disease mechanism, but this synonymous variant is not a generic PVS1-eligible loss-of-function variant.

Computational splice prediction does not support a damaging effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

Met · 2

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 8.17254e-06
  • gnomAD v4.1 total AF 8.06613e-06
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingAvailable 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • Synonymous consequence p.(Ala409=)
Sources
spliceai ↗

Not met · 8 · evaluated, threshold not reached

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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 fallback via ClinGen SVI PVS1 recommendations
Evidence considered
  • Gene-level loss-of-function mechanism supported for CUX1
  • Variant annotated as p.(Ala409=)
  • Generic PVS1 scaffold does not place this variant in a PVS1-eligible bucket
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:37644171 ↗PMID:25645650 ↗PMID:38443608 ↗
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. Details ▾Hide ▴
Evidence considered
  • No hotspot row identified at A409
  • No variant-specific oncogenic evidence identified
Sources
hotspots ↗oncokb ↗
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. Details ▾Hide ▴
Evidence considered
  • SpliceAI DS_AG 0.00
  • SpliceAI DS_AL 0.00
  • SpliceAI DS_DG 0.00
  • SpliceAI DS_DL 0.00
  • REVEL not available
  • BayesDel not available
  • HCI prior not available
Sources
spliceai ↗
PP5 No reputable external classification source identifying this variant as pathogenic was found; the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission identified
Sources
clinvar ↗
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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF 8.06613e-06
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 highest subpopulation AF 1.3344e-05
Sources
gnomad_v4 ↗
BP6 No reputable external classification source identifying this variant as benign was found; the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission identified
Sources
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. Details ▾Hide ▴
Evidence considered
  • Synonymous consequence p.(Ala409=)
  • SpliceAI max delta score 0.00
Still missing
  • Nucleotide conservation data
Sources
spliceai ↗

Not assessed · 11 · no assessment recorded

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo report identified in the reviewed evidence
Still missing
  • Case-level parental testing data
  • Phenotype-specific de novo report
PS3 No well-established functional study was identified for this exact variant. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional evidence retrieved
Still missing
  • Variant-specific RNA or other validated functional assay
Sources
oncokb ↗
PS4 No case enrichment, case-control, or multiple affected-individual observations were identified for this variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • Affected-individual observations
  • Case-control or enrichment data
Sources
clinvar ↗
PM6 No presumed de novo occurrence was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No presumed de novo report identified
Still missing
  • Case report describing de novo occurrence without full parental confirmation
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No cosegregation report identified
Still missing
  • Family segregation data
PP4 No phenotype information was provided that is sufficiently specific to assess PP4 for this variant. Details ▾Hide ▴
Evidence considered
  • No case phenotype available for review
Still missing
  • Phenotype data
  • Phenotype-to-gene specificity assessment
BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency or zygosity sufficient to support BS2. Details ▾Hide ▴
Evidence considered
  • No homozygotes observed in gnomAD v2.1 or v4.1
Still missing
  • Robust healthy adult observation data relevant to the disease context
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study was identified showing no damaging effect for this exact variant. Details ▾Hide ▴
Evidence considered
  • No benign functional assay identified
  • SpliceAI predicts no significant splice impact
Still missing
  • Variant-specific RNA or other validated benign functional assay
Sources
spliceai ↗
BS4 No family data were identified showing lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No nonsegregation report identified
Still missing
  • Informative nonsegregation data
BP2 No phase data were identified to assess BP2. Details ▾Hide ▴
Evidence considered
  • No cis/trans data identified
Still missing
  • Phase information with another relevant variant
BP5 No alternate molecular explanation was identified that would allow assessment of BP5. Details ▾Hide ▴
Evidence considered
  • No alternate cause data available
Still missing
  • Independent established cause for the phenotype
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this is a synonymous variant and no evidence was identified that it produces the same amino acid change as an established pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Synonymous consequence p.(Ala409=)
  • No ClinVar record identified for this variant
Sources
clinvar ↗
PM3 N/ANo recessive disease context or trans observation data were identified to support PM3 for this variant. Details ▾Hide ▴
Evidence considered
  • No trans data identified
PM4 N/APM4 is not applicable because this variant is a synonymous substitution and does not change protein length. Details ▾Hide ▴
Evidence considered
  • Synonymous consequence p.(Ala409=)
PM5 N/APM5 is not applicable because this is not a missense variant, and same-residue PM5 comparator logic could not be applied. Details ▾Hide ▴
Evidence considered
  • No classic same-residue PM5 candidates identified
  • Synonymous consequence prevents missense comparator use
Sources
pm5_candidates
PP2 N/APP2 is not applicable because this is not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous consequence p.(Ala409=)
BP1 N/ABP1 is not applicable because this is not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous consequence p.(Ala409=)
BP3 N/ABP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Synonymous single-nucleotide substitution

Identifiers

Gene
CUX1
Transcript
NM_001202543.1
Coding (HGVS c.)
NM_001202543.1:c.1227G>A
Protein (HGVS p.)
NP_001189472.1:p.(Ala409=)
GRCh38
chr7:102195575 G>A
GRCh37
chr7:101838855 G>A

Gene diagram

Every interpreted variant in CUX1, mapped onto the exon structure of NM_001202543.1. Select a row to find it on the plot.

CUX1NM_001202543.1
Fetching transcript structure from UCSC…
gnomAD v4.1 13 / 1,611,678 alleles AF 8.07e-06 · 0 homozygotes · FAF 5.43e-06
gnomAD v2.1 2 / 244,722 alleles AF 8.17e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 8.1e-06 · 13 / 1,611,678 alleles · 0 hom · FAF 5.4e-06
African/African American1 / 74,940 1.3e-05
European (non-Finnish)12 / 1,179,520 1e-05
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 8.2e-06 · 2 / 244,722 alleles · 0 hom
African/African American1 / 15,708 6.4e-05
European (non-Finnish)1 / 110,668 9e-06
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD 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).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingAvailable 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • Synonymous consequence p.(Ala409=)
Sources
spliceai ↗
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. Details ▾Hide ▴
Evidence considered
  • SpliceAI DS_AG 0.00
  • SpliceAI DS_AL 0.00
  • SpliceAI DS_DG 0.00
  • SpliceAI DS_DL 0.00
  • REVEL not available
  • BayesDel not available
  • HCI prior not available
Sources
spliceai ↗
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. Details ▾Hide ▴
Evidence considered
  • Synonymous consequence p.(Ala409=)
  • SpliceAI max delta score 0.00
Still missing
  • Nucleotide conservation data
Sources
spliceai ↗

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 13 / 1,611,678 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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).

ClinVar

This variant is absent from ClinVar.

In silico

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

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.