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AXIN2c.432T>CBenign
Print report
Variant interpretation report

AXIN2 c.432T>C, p.(Ile144=)

NM_004655.4:c.432T>C NP_004646.3:p.(Ile144=) View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

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

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About AXIN2

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: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone

Variant allele frequency far exceeds the BA1 threshold of 1%. gnomAD v2.1: AF=4.39% (12,423/282,858 alleles, 675 homozygotes); highest population frequency is East Asian at 16.63% (3,319/19,952 alleles, 290 homozygotes); grpmax FAF=16.20%. gnomAD v4.1: AF=2.01% (32,503/1,613,946 alleles, 1,500 homozygotes); East Asian AF=16.48%; grpmax FAF=16.16%.

BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact. SpliceAI predicts no splicing effect (max delta=0.00). REVEL and BayesDel are not scored for synonymous variants but the absence of any predicted effect across available tools is consistent with a benign impact.

BP7Supporting
BP7 · supporting

Synonymous variant (NP_004646.3:p.(Ile144=)) with no predicted splice impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences and no cryptic splice site creation. The nucleotide position shows high population variation (AF=4.39%), consistent with low evolutionary constraint.

Recorded classification: Benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BP4 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 2 supporting benign, which maps to Benign.

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
32,503 / 1,613,946 alleles

gnomAD v4.1: 32,503 / 1,613,946 alleles. Recorded AF 0.0201388. Recorded homozygote count 1500.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0439196; MAF= 4.39196%, 12423/282858 alleles, homozygotes = 675) and has highest observed frequency in the East Asian population (AF= 0.166349; MAF= 16.63492%, 3319/19952 alleles, homozygotes = 290); grpmax FAF= 0.162031.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.02845351867940921, 524/18416 alleles, homozygotes = 21).

Applied · BA1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
15 reported laboratory submissions

15 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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
32 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV61056425, n = 32 times).

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.

26 criteria with recorded statuses: 3 met · 14 not met · 1 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_004655.4:c.432T>C (p.Ile144=) is a synonymous variant in AXIN2. This variant is present at extremely high frequency in population databases: gnomAD v2.1 overall allele frequency is 4.39% (12,423/282,858 alleles) with 675 homozygotes, and the East Asian subpopulation frequency is 16.63% (3,319/19,952 alleles) with 290 homozygotes. gnomAD v4.1 corroborates with overall AF=2.01% (32,503/1,613,946 alleles, 1,500 homozygotes) and East Asian AF=16.48%. The grpmax filtering allele frequency is 16.2%, far exceeding the 1% BA1 stand-alone benign threshold.

SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), consistent with a synonymous change that does not alter the amino acid sequence (p.Ile144=) and does not create or disrupt splice sites.

This variant has been classified as Benign in ClinVar (VariationID 259515) by 15 clinical laboratories with criteria provided. While the review status is single submitter (1-star), the unanimous benign classification across multiple submitters is consistent with the population frequency and in silico evidence.

Overall classification: Benign. BA1 (stand-alone benign) is met based on allele frequency far exceeding 1%. One stand-alone benign criterion is sufficient for a Benign classification per ACMG/AMP 2015 combination rules. Additional supporting benign criteria BP4 and BP7 further reinforce the benign classification.

Met · 3

BA1 Stand aloneVariant allele frequency far exceeds the BA1 threshold of 1%. gnomAD v2.1: AF=4.39% (12,423/282,858 alleles, 675 homozygotes); highest population frequency is East Asian at 16.63% (3,319/19,952 alleles, 290 homozygotes); grpmax FAF=16.20%. gnomAD v4.1: AF=2.01% (32,503/1,613,946 alleles, 1,500 homozygotes); East Asian AF=16.48%; grpmax FAF=16.16%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: overall AF=4.39%
  • EAS AF=16.63%
  • 675 homozygotes
  • gnomAD v4.1: overall AF=2.01%
  • EAS AF=16.48%
  • 1500 homozygotes.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact. SpliceAI predicts no splicing effect (max delta=0.00). REVEL and BayesDel are not scored for synonymous variants but the absence of any predicted effect across available tools is consistent with a benign impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00
  • synonymous variant with no predicted splice impact.
Still missing
  • REVEL and BayesDel not available for synonymous variants
  • conservation data not explicitly scored.
Sources
spliceai ↗
BP7 SupportingSynonymous variant (NP_004646.3:p.(Ile144=)) with no predicted splice impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences and no cryptic splice site creation. The nucleotide position shows high population variation (AF=4.39%), consistent with low evolutionary constraint. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00
  • synonymous variant p.Ile144=
  • high population frequency supports low conservation.
Still missing
  • Formal nucleotide conservation score not available
  • but high population AF strongly suggests low constraint.
Sources
spliceai ↗gnomad_v2 ↗

Not met · 14 · evaluated, threshold not reached

PS2 No de novo confirmation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo studies identified for NM_004655.4:c.432T>C.
PS3 No variant-specific functional studies identified for this synonymous variant (p.Ile144=). No experimental data demonstrating a damaging functional effect exist. Details ▾Hide ▴
Still missing
  • No functional studies available for this synonymous variant.
PM2 Variant is common in population databases. gnomAD v2.1 AF=4.39% (12,423/282,858 alleles, 675 homozygotes), far exceeding the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=4.39%
  • gnomAD v4.1 AF=2.01%. Far above PM2 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 No de novo confirmation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo studies identified for NM_004655.4:c.432T>C.
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation studies identified.
PP3 Multiple in silico tools predict no impact. SpliceAI max delta score is 0.00 (no splice effect). REVEL and BayesDel not available for this synonymous variant. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00
  • REVEL/BayesDel not available (synonymous).
Still missing
  • REVEL and BayesDel not scored for synonymous variants.
Sources
spliceai ↗
PP4 No patient phenotype or family history data available for assessment. Details ▾Hide ▴
Still missing
  • No proband phenotype or clinical context provided.
PP5 ClinVar classification is Benign (VariationID 259515, 15 clinical laboratories), not Pathogenic. Review status is criteria provided, single submitter (1-star), which does not meet the 3-star expert panel threshold required for automatic PP5 application. Details ▾Hide ▴
Evidence considered
  • ClinVar: Benign
  • criteria provided single submitter (1-star). Does not meet PP5 requirements.
Sources
clinvar ↗
BS2 Although 675 homozygotes in gnomAD v2.1 suggest observation in healthy individuals, no phenotype-confirmed healthy adult data with full penetrance expectation is available. Population frequency alone is captured under BA1. Details ▾Hide ▴
Evidence considered
  • 675 homozygotes in gnomAD v2.1 are suggestive but lack phenotype confirmation for BS2.
Still missing
  • No phenotype-confirmed healthy adult observation for this variant.
BS3 No functional studies demonstrating no damaging effect are available for this synonymous variant. Details ▾Hide ▴
Still missing
  • No functional studies identified for this variant.
BS4 No segregation data available for assessment of lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation studies identified.
BP2 No data available on observation in trans with a pathogenic variant. Details ▾Hide ▴
Still missing
  • No in trans observation data available.
BP5 No evidence that this variant was found in a case with an alternate molecular basis for disease. COSMIC reports 32 somatic observations (COSV61056425) but this does not satisfy BP5 requirements. Details ▾Hide ▴
Still missing
  • No case with alternate molecular basis identified.
BP6 ClinVar classification is Benign (VariationID 259515, 15 clinical laboratories), but the review status is criteria provided, single submitter (1-star). BP6 automatic application requires 3-star expert panel status. This does not qualify. Details ▾Hide ▴
Evidence considered
  • ClinVar Benign
  • single submitter (1-star). Does not meet 3-star EP threshold for BP6.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

BS1 Superseded by BA1 (stand-alone benign). Variant frequency exceeds both BS1 (>0.3%) and BA1 (>1%) thresholds; BA1 provides the stronger level of evidence. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (NP_004646.3:p.(Ile144=)); does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution at c.432T>C results in p.Ile144= with no predicted null effect.
Sources
pvs1_variant_assessment
PS1 N/ASynonymous variant produces no amino acid change (p.Ile144=); no comparator pathogenic missense change at this position exists. Details ▾Hide ▴
Evidence considered
  • Synonymous variant with no amino acid alteration.
PS4 N/AVariant is present at high population frequency (AF=4.39% gnomAD v2.1, 16.63% East Asian, 675 homozygotes), inconsistent with pathogenicity. Prevalence comparison in affected vs. controls is not meaningful. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 12423/282858 alleles (AF=4.39%)
  • 675 homozygotes.
Sources
gnomad_v2 ↗
PM1 N/ASynonymous variant (p.Ile144=) does not alter the amino acid sequence; even if located within a critical functional domain, no domain disruption occurs. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no amino acid change
  • no domain disruption.
PM5 N/ASynonymous variant produces no amino acid change (p.Ile144=); no comparator missense variant at this residue exists. PM5 candidate harvesting confirmed not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no same-residue pathogenic missense comparator available.
Sources
pm5_candidates
PP2 N/ASynonymous variant, not a missense change. PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PP2 restricted to missense.
BP1 N/ASynonymous variant, not a missense change. BP1 applies only to missense variants in genes where a truncating mechanism is the primary cause of disease. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • BP1 restricted to missense.
PS5 N/ASynonymous variant produces no amino acid change (p.Ile144=); no different amino acid change at the same codon can exist for comparison. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no amino acid substitution to compare.

Identifiers

Gene
AXIN2
Transcript
NM_004655.4
Coding (HGVS c.)
NM_004655.4:c.432T>C
Protein (HGVS p.)
NP_004646.3:p.(Ile144=)
GRCh38
chr17:65558189 A>G
GRCh37
chr17:63554307 A>G
ClinVar
259515
COSMIC
COSV61056425

Gene diagram

Every interpreted variant in AXIN2, mapped onto the exon structure of NM_004655.4. Select a row to find it on the plot.

AXIN2NM_004655.4
Fetching transcript structure from UCSC…
gnomAD v4.1 32,503 / 1,613,946 alleles AF 0.0201 · 1500 homozygotes · FAF 0.162
gnomAD v2.1 12,423 / 282,858 alleles AF 0.0439 · 675 homozygotes · FAF 0.162
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.02 · 32503 / 1,613,946 alleles · 1500 hom · FAF 0.16
East Asian7394 / 44,870 0.16610 hom
Admixed American6967 / 60,004 0.12480 hom
African/African American5583 / 74,942 0.074212 hom
South Asian3666 / 91,052 0.04116 hom
European (Finnish)1969 / 64,012 0.03131 hom
Remaining individuals1382 / 62,506 0.02235 hom
Middle Eastern88 / 6,062 0.0152 hom
Ashkenazi Jewish223 / 29,606 0.0075
European (non-Finnish)5231 / 1,179,980 0.004414 hom
0 alternate alleles recorded in 1 other group: Amish.

gnomAD v2.1

AF 0.044 · 12423 / 282,858 alleles · 675 hom · FAF 0.16
East Asian3319 / 19,952 0.17290 hom
Admixed American4256 / 35,440 0.12269 hom
African/African American1815 / 24,952 0.07354 hom
South Asian1258 / 30,616 0.04141 hom
European (Finnish)818 / 25,124 0.03315 hom
Remaining individuals194 / 7,224 0.0271 hom
Ashkenazi Jewish78 / 10,370 0.0075
European (non-Finnish)685 / 129,180 0.00535 hom

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.0201388; MAF= 2.01388%, 32503/1613946 alleles, homozygotes = 1500) and has highest observed frequency in the East Asian population (AF= 0.164787; MAF= 16.47872%, 7394/44870 alleles, homozygotes = 610); grpmax FAF= 0.161647.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0439196; MAF= 4.39196%, 12423/282858 alleles, homozygotes = 675) and has highest observed frequency in the East Asian population (AF= 0.166349; MAF= 16.63492%, 3319/19952 alleles, homozygotes = 290); grpmax FAF= 0.162031.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.02845351867940921, 524/18416 alleles, homozygotes = 21).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact. SpliceAI predicts no splicing effect (max delta=0.00). REVEL and BayesDel are not scored for synonymous variants but the absence of any predicted effect across available tools is consistent with a benign impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00
  • synonymous variant with no predicted splice impact.
Still missing
  • REVEL and BayesDel not available for synonymous variants
  • conservation data not explicitly scored.
Sources
spliceai ↗
BP7 SupportingSynonymous variant (NP_004646.3:p.(Ile144=)) with no predicted splice impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences and no cryptic splice site creation. The nucleotide position shows high population variation (AF=4.39%), consistent with low evolutionary constraint. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00
  • synonymous variant p.Ile144=
  • high population frequency supports low conservation.
Still missing
  • Formal nucleotide conservation score not available
  • but high population AF strongly suggests low constraint.
Sources
spliceai ↗gnomad_v2 ↗
PP3 Multiple in silico tools predict no impact. SpliceAI max delta score is 0.00 (no splice effect). REVEL and BayesDel not available for this synonymous variant. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00
  • REVEL/BayesDel not available (synonymous).
Still missing
  • REVEL and BayesDel not scored for synonymous variants.
Sources
spliceai ↗

Statement

In silico

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

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological framework paper describing variant classification criteria. NM_004655.4:c.432T>C was not identified in this paper.
    Does not name this variant
    PMID 25741868 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline for cancer predisposition assessment referral indications. This is a clinical practice guideline. NM_004655.4:c.432T>C was not identified in this paper.
    Does not name this variant
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological framework paper. NM_004655.4:c.432T>C was not identified in this paper.
    Does not name this variant
    PMID 28492532 ↗

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

gnomAD v4.1 32,503 / 1,613,946 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 15 Benign 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= 0.0201388; MAF= 2.01388%, 32503/1613946 alleles, homozygotes = 1500) and has highest observed frequency in the East Asian population (AF= 0.164787; MAF= 16.47872%, 7394/44870 alleles, homozygotes = 610); grpmax FAF= 0.161647.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0439196; MAF= 4.39196%, 12423/282858 alleles, homozygotes = 675) and has highest observed frequency in the East Asian population (AF= 0.166349; MAF= 16.63492%, 3319/19952 alleles, homozygotes = 290); grpmax FAF= 0.162031.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.02845351867940921, 524/18416 alleles, homozygotes = 21).

ClinVar

This variant has been reported in ClinVar as Benign (15 clinical laboratories). (ClinVarID = 259515)

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 previously been reported in somatic cancers (COSMIC; COSV61056425, n = 32 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.