AXIN2 c.1386C>T, p.Pro462=
NM_004655.4:c.1386C>T
COSMIC ID: COSM3749411
Likely Benign
This synonymous AXIN2 variant is extremely common in population databases, observed in homozygotes at high frequency, lacks functional or clinical evidence of pathogenicity, and has multiple benign lines of evidence (BA1 stand-alone, BS1, BS2, BP4, BP6, BP7), supporting a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
AXIN2
Transcript
NM_004655.4
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004655.3 | Alternative | 11 exons | Reverse |
| NM_004655.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_004655.4:c.1386C>T
Protein Change
P462=
Location
Exon 6
(Exon 6 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM3749411
Variant interpretation based on transcript NM_004655.4
Genome Browser
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HGVS InputNM_004655:c.1386C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
58.8%
Common
Highest in Population
Ashkenazi Jewish
71.9%
Common
Global: 58.8%
Ashkenazi Jewish: 71.9%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 217042Alt: 127718Homozygotes: 39453
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 58.8%, 127718/217042 alleles, homozygotes = 39453) and at a higher frequency in the Ashkenazi Jewish population (MAF= 71.9%, 6678/9284 alleles, homozygotes = 2391). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
1 publications
Benign
Based on 17 submitter reviews in ClinVar
Submitter Breakdown
17 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Variant summary: The AXIN2 c.1386C>T variant affects a non-conserved nucleotide, resulting in no amino acid change. Mutation Taster predicts the variant is a polymorphism, and 5/5 Alamut algorithms predict no significant change to splicing. This variant was found in 35556/57014 control chromosomes (11148 homozygotes) at a frequency of 0.6236363, which is about 4390 times of the maximal expected frequency of a pathogenic ACIN2 allele (0.0001421), suggesting this variant is benign. The variant has been reported to possibly be associated with astrocytoma, however the odds ratio was not believable and the sample size was relatively small (Gunes_Mol Med Reports_2010). Taken together, this variant was classified as benign.
Clinical Statement
This variant has been reported in ClinVar as Benign (17 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.30
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PVS1 is: "PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a synonymous change (c.1386C>T, p.P462=) and does not introduce a null effect. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: it is a synonymous change and does not alter the amino acid. Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because functional data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS4 is: "PS4 – Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data indicating enrichment in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: it is synonymous and not in a known functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: MAF = 58.8% in gnomAD (127718/217042 alleles), with 39453 homozygotes. Therefore, this criterion is not applied because the variant is common in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no trans observations with pathogenic variants reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a synonymous substitution and does not change protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: "PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is synonymous and not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico predictors are benign (CADD=0.30, SpliceAI=0.01). Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP4 is: "PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: sources report benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines, the rule/finding for BA1 is: "BA1 – Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF = 58.8% in gnomAD with 39453 homozygotes, far exceeding any disease threshold. Therefore, this criterion is applied at Stand Alone strength because the allele frequency is too high to be pathogenic.
BS1
BS1 (Strong)
According to standard ACMG guidelines, the rule/finding for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF = 58.8% in gnomAD, greatly exceeding expected frequency. Therefore, this criterion is applied at Strong strength because the allele frequency is far above that expected for a pathogenic variant.
BS2
BS2 (Strong)
According to standard ACMG guidelines, the rule/finding for BS2 is: "BS2 – Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: 39453 homozygotes in gnomAD and high frequency in general populations with no disease association. Therefore, this criterion is applied at Strong strength because it is observed in healthy individuals at high frequency.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS4 is: "BS4 – Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: "BP1 – Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP2 is: "BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no such observations reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a single-nucleotide substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule/finding for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: CADD score=0.30 and SpliceAI=0.01 predicting no impact. Therefore, this criterion is applied at Supporting strength because computational data indicate no functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case information. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule/finding for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar lists this variant as Benign by 17 clinical laboratories, but primary evidence is unavailable. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule/finding for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is synonymous (p.P462=) and SpliceAI predicts no splicing impact (score=0.01). Therefore, this criterion is applied at Supporting strength.