NM_004655.4:c.1908-23C>T

AXIN2 · NP_004646.3:p.? · NM_004655.4

GRCh37: chr17:63532694 G>A · GRCh38: chr17:65536576 G>A

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

PM2 supporting

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.?

gnomAD AF

3.723114459707835e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004655.4:c.1908-23C>T is a deep intronic variant in AXIN2 located 23 bp upstream of exon 7.

SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), providing no computational evidence of altered splicing.

The variant is present in gnomAD at extremely low frequency: v2.1 AF = 0.00109% (3/274,000 alleles) and v4.1 AF = 0.00037% (6/1,611,554 alleles), with no homozygotes observed (PM2_supporting). However, rarity alone is limited by the absence of a predicted functional consequence.

This variant is absent from ClinVar, and no publications, functional studies, segregation data, or de novo observations are available.

AXIN2 loss of function is a recognized germline disease mechanism associated with colorectal polyposis and tooth agenesis, but no variant-specific evidence exists to support pathogenicity of this deep intronic substitution.

Based on the generic ACMG/AMP 2015 classification framework, the available evidence (PM2_supporting only) is insufficient to classify this variant as pathogenic or likely pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_004655.4:c.1908-23C>T is a deep intronic substitution located 23 bp upstream of exon 7. It does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework is not applicable to this variant class.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No known pathogenic variant has been reported at this nucleotide position (c.1908-23) in ClinVar or the literature. PS1 requires a known pathogenic variant at the same nucleotide position.	clinvar
PS2	Not met	No de novo observation has been reported for this variant. PS2 requires confirmation of de novo occurrence in a patient with disease and no family history.
PS3	Not met	No functional studies have been performed on NM_004655.4:c.1908-23C>T. The variant has not been directly tested in any experimental assay, nor does it fall within a systematically characterized range. No REVEL or BayesDel scores are available for this intronic variant.
PS4	Not met	No case-control or statistical enrichment data are available for this variant. PS4 requires significantly increased prevalence in affected individuals compared to controls.
PS5	Not met	PS5 requires a reputable source (e.g., clinical diagnostic laboratory) to have previously classified this variant as pathogenic. This variant is absent from ClinVar and has no prior clinical classifications.	clinvar
PM1	Not met	NM_004655.4:c.1908-23C>T is located in intron 7, 23 bp upstream of the exon boundary. SpliceAI predicts no splicing impact (max delta = 0.00), so there is no evidence that this variant disrupts a critical functional domain. PM1 requires the variant to reside in a mutational hotspot or critical functional domain.	spliceai
PM2	Met	NM_004655.4:c.1908-23C>T is present in gnomAD at extremely low frequency: v2.1 AF = 0.00109% (3/274,000 alleles), v4.1 AF = 0.00037% (6/1,611,554 alleles), with no homozygotes observed. Both frequencies are well below the 0.1% PM2 threshold for dominant disorders. However, the variant is a deep intronic substitution with no predicted splicing impact (SpliceAI delta = 0.00), which limits the weight of population rarity as evidence of pathogenicity.	gnomad_v2 gnomad_v4
PM5	N/A	This is an intronic variant with no protein change; no same-residue pathogenic missense comparator can be identified. PM5 requires a different amino acid change at the same residue classified as pathogenic.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires confirmation of de novo occurrence with confirmed maternity and paternity.
PP1	Not met	No segregation data are available for this variant. PP1 requires co-segregation with disease in multiple affected family members.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a missense variant.
PP3	Not met	SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No HCI prior probability is available for AXIN2. Multiple lines of computational evidence do not support a deleterious effect.	spliceai
PP4	Not met	No phenotype or clinical data are available for the individual(s) carrying this variant. PP4 requires the patient's phenotype or family history to be highly specific for the disease associated with the gene.
PP5	N/A	This variant is absent from ClinVar. PP5 requires a ClinVar entry from a reputable source (at least 3-star expert panel) classifying the variant as pathogenic. No ClinVar record exists for this variant.	clinvar
BA1	Not met	The highest observed population allele frequency is 0.00246% (NFE, gnomAD v2.1), which is well below the 1% BA1 threshold. The variant does not qualify as a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The highest observed population allele frequency is 0.00246% (NFE, gnomAD v2.1), which is well below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on observation of this variant in healthy adults for a fully penetrant dominant disorder. The gnomAD observations (3 heterozygous in v2.1, 6 heterozygous in v4.1) do not include phenotype data.
BS3	Not met	No functional studies demonstrating no deleterious effect have been performed on this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.
BS4	Not met	No segregation data are available. BS4 requires lack of segregation with disease in affected family members.
BP1	N/A	BP1 applies specifically to missense variants in genes where truncating variants are the primary pathogenic mechanism. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a missense variant.
BP2	Not met	No data available on co-occurrence with a known pathogenic variant. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic variant for a fully penetrant recessive disorder.
BP3	N/A	Skipped — trivially not applicable.
BP4	Not met	SpliceAI predicts no splicing impact (max delta = 0.00) for this deep intronic variant. However, BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI is available for this intronic variant; REVEL and BayesDel are not applicable. A single line of evidence does not meet the BP4 threshold.	spliceai
BP5	N/A	This variant is absent from ClinVar. BP5 requires a ClinVar record from a reputable source classifying the variant as benign or likely benign. No ClinVar entry exists.	clinvar
BP6	N/A	This variant is absent from ClinVar. BP6 requires a ClinVar entry from a reputable source (at least 3-star expert panel) classifying the variant as benign. No ClinVar record exists.	clinvar
BP7	N/A	BP7 applies specifically to synonymous coding variants for which splicing prediction algorithms predict no impact. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a coding synonymous variant.

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