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.1 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.2 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.3 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.4
AXIN2
Final classification
Benign
AXIN2 c.432T>C · p.Ile144=
AXIN2
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.
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.
Classification rationale
BA1BP4BP7
Benign
AXIN2 c.432T>C
BA1 + BP4 + BP7
→
Benign
Gene diagram
· NM_004655.4 · variants mapped to exon structure
AXIN2
NM_004655.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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%.
gnomAD v2.1: overall AF=4.39%EAS AF=16.63%675 homozygotes
✓
BP4
supporting
Benign
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.
SpliceAI max delta=0.00synonymous variant with no predicted splice impact.
✓
BP7
supporting
Benign
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.
SpliceAI max delta=0.00synonymous variant p.Ile144=high population frequency supports low conservation.
Assessed · not applied
Pathogenic
PS2
No de novo confirmation data available for this variant.
PS3
No variant-specific functional studies identified for this synonymous variant (p.Ile144=).
PM2
Variant is common in population databases.
PM6
No de novo confirmation data available for this variant.
PP1
No co-segregation data available for this variant.
PP3
Multiple in silico tools predict no impact.
PP4
No patient phenotype or family history data available for assessment.
PP5
ClinVar classification is Benign (VariationID 259515, 15 clinical laboratories), not Pathogenic.
Benign
BS1
Superseded by BA1 (stand-alone benign).
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.
BS3
No functional studies demonstrating no damaging effect are available for this synonymous variant.
BS4
No segregation data available for assessment of lack of co-segregation with disease.
BP2
No data available on observation in trans with a pathogenic variant.
BP5
No evidence that this variant was found in a case with an alternate molecular basis for disease.
BP6
ClinVar classification is Benign (VariationID 259515, 15 clinical laboratories), but the review status is criteria provided, single submitter (1-star).
N/A · 7
PVS1 · PS1 · PS4 · PM1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.02845351867940921, 524/18416 alleles, homozygotes = 21).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
2%
· 32503 / 1,613,946
1500 hom · FAF 16%
1500 hom · FAF 16%
East Asian 7394 / 44,870 |
16% 610 hom |
Admixed American 6967 / 60,004 |
12% 480 hom |
African/African American 5583 / 74,942 |
7.4% 212 hom |
South Asian 3666 / 91,052 |
4% 116 hom |
European (Finnish) 1969 / 64,012 |
3.1% 31 hom |
Remaining individuals 1382 / 62,506 |
2.2% 35 hom |
Middle Eastern 88 / 6,062 |
1.5% 2 hom |
Ashkenazi Jewish 223 / 29,606 |
0.75% |
European (non-Finnish) 5231 / 1,179,980 |
0.44% 14 hom |
+ 1 not observed (Amish)
gnomAD v2.1
4.4%
· 12423 / 282,858
675 hom · FAF 16%
675 hom · FAF 16%
East Asian 3319 / 19,952 |
17% 290 hom |
Admixed American 4256 / 35,440 |
12% 269 hom |
African/African American 1815 / 24,952 |
7.3% 54 hom |
South Asian 1258 / 30,616 |
4.1% 41 hom |
European (Finnish) 818 / 25,124 |
3.3% 15 hom |
Remaining individuals 194 / 7,224 |
2.7% 1 hom |
Ashkenazi Jewish 78 / 10,370 |
0.75% |
European (non-Finnish) 685 / 129,180 |
0.53% 5 hom |
gnomAD Canada 🇨🇦
2.8%
· 524 / 18,416
21 hom · FAF 12%
21 hom · FAF 12%
East Asian 181 / 1,338 |
14% 12 hom |
Latino/Admixed American 91 / 838 |
11% 4 hom |
African/African American 91 / 1,018 |
8.9% 3 hom |
South Asian 51 / 1,362 |
3.7% 1 hom |
Middle Eastern 3 / 144 |
2.1% |
Remaining individuals 18 / 1,136 |
1.6% |
European (non-Finnish) 84 / 11,740 |
0.72% |
Ashkenazi Jewish 5 / 832 |
0.6% 1 hom |
+ 1 not observed (European (Finnish))
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61056425, n = 32 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗
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.
CLINVAR
25394175 ↗
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.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR