NM_001904.4:c.269G>A

CTNNB1 · NP_001895.1:p.(Arg90Gln) · NM_001904.4

GRCh37: chr3:41266472 G>A · GRCh38: chr3:41224981 G>A

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 moderate

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Arg90Gln)

gnomAD AF

6.1959327419109e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001904.4:c.269G>A (p.Arg90Gln) is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada with 1 allele out of 1,613,962 in gnomAD v4.1 (AF 0.000062%), meeting PM2 at moderate strength.

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (VariationID 1378784).

In silico predictors are equivocal (REVEL 0.455, BayesDel 0.221, SpliceAI delta 0.0) and do not meet thresholds for PP3 or BP4.

This variant has been observed in somatic cancers (COSMIC COSV62707932, n = 2); no germline functional evidence is available.

No de novo, segregation, case-control, or functional data are available for this variant. Multiple criteria remain unassessed.

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	PVS1 applies to null variants (nonsense, frameshift, canonical splice). NM_001904.4:c.269G>A is a missense variant (p.Arg90Gln) and does not fall into any null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No established pathogenic missense variant at the same amino acid residue (Arg90) is available for comparison. Same-residue comparator search returned no candidates.
PS2	Not assessed	No de novo observation with confirmed maternity and paternity is available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a damaging effect of NM_001904.4:c.269G>A (p.Arg90Gln). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No published functional data were identified.	oncokb
PS4	Not assessed	Prevalence in affected individuals versus controls has not been established. A single ClinVar submission (Labcorp/Invitae, VUS) is insufficient for case-control assessment.	clinvar
PS5	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance from a single submitter.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. Residue Arg90 is not identified as a recurrently mutated position in CTNNB1.
PM2	Met	NM_001904.4:c.269G>A is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada; 1 allele out of 1,613,962 in gnomAD v4.1 (AF = 6.2e-7, 0.000062%), well below the 0.1% PM2 threshold. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No established pathogenic missense variant at the same amino acid residue (Arg90) has been identified. PM5 candidate harvesting returned zero comparators.	pm5_candidates
PM6	Not assessed	No de novo observation (without confirmation of maternity/paternity) is available for this variant.
PP1	Not assessed	No co-segregation data with disease in multiple affected family members is available.
PP2	Not assessed	Insufficient data to assess whether CTNNB1 has a low rate of benign missense variation (e.g., gnomAD missense Z-score or constraint metric not available in this case). While missense variants in CTNNB1 are a known disease mechanism in CTNNB1 syndrome, formal constraint metrics are absent.
PP3	Not met	In silico predictors do not reach damaging thresholds: REVEL score 0.455 is below the 0.5 threshold, BayesDel score 0.221 is below the 0.27 threshold, and SpliceAI predicts no splice impact (max delta = 0.0). No multiple lines of computational evidence support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess phenotypic specificity for CTNNB1 syndrome.
PP5	Not met	No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Labcorp/Invitae) classifies it as Uncertain significance.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No data available regarding observation of this variant in healthy adults where full penetrance of CTNNB1 syndrome would be expected at an early age.
BS3	Not assessed	No well-established functional studies demonstrate no damaging effect of this variant. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not assessed	No non-segregation data with disease phenotype in multiple affected family members is available.
BP1	Not met	BP1 applies when primarily truncating variants cause disease in a gene. In CTNNB1, missense variants are a well-established disease mechanism — both missense and truncating variants cause CTNNB1 syndrome (PMIDs 33350591, 36083290).
BP2	Not assessed	No data available regarding observation in trans with a known pathogenic CTNNB1 variant.
BP4	Not met	Multiple lines of computational evidence do not consistently suggest no impact on the gene product. SpliceAI predicts no splice effect (delta = 0.0), but REVEL is borderline (0.455, just below 0.5) and BayesDel (0.221) does not clearly support benign impact. The evidence is equivocal.	revel bayesdel spliceai
BP5	Not assessed	No data available regarding a case with an alternative molecular cause for disease.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar reports Uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_001904.4:c.269G>A is a missense variant (p.Arg90Gln), not synonymous.
BP3	N/A	BP3 applies to in-frame deletions or insertions in non-repeat regions. This variant is a single-nucleotide missense substitution.
PM3	N/A	PM3 applies to recessive disorders. CTNNB1 syndrome is an autosomal dominant disorder.
PM4	N/A	PM4 applies to protein-length-altering variants (in-frame indels, stop-loss). This variant is a single-nucleotide missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.