Variant classification summary

NM_001904.4:c.420T>C

CTNNB1 · NP_001895.1:p.(Ile140=) · NM_001904.4

GRCh37: chr3:41266623 T>C · GRCh38: chr3:41225132 T>C

Gene: CTNNB1 Transcript: NM_001904.4

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP7 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Ile140=)

gnomAD AF

0.0009262437377869032 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-alone Benign): the variant is common in general-population databases, with a maximum allele frequency of about 1.5% (African/African American) - far above the 1% threshold and inconsistent with a cause of a severe, predominantly de novo dominant disorder.

2

BS1 (Strong Benign): population allele frequency (up to about 1.5%) far exceeds expectation for CTNNB1 syndrome, and the presence of homozygotes is incompatible with a fully penetrant dominant disease allele.

3

BP7 (Supporting Benign): synonymous (silent) change with no predicted splicing effect (SpliceAI max delta 0.13, below the splice-altering threshold).

4

Overall classification: Benign. Under the ACMG/AMP 2015 rules, the stand-alone BA1 criterion alone is sufficient for Benign; BS1 and BP7 additionally reinforce the call.

Final determination: Under the generic ACMG/AMP 2015 combination rules, a single stand-alone benign criterion (BA1: maximum population AF ~1.5% exceeds the 1% threshold) is sufficient for Benign, and the additional BS1 (strong) plus BP7 (supporting) benign criteria are consistent with that call.

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	Not applicable: this is a synonymous (silent) change that leaves the protein sequence unchanged (p.Ile140=). PVS1 requires a null variant such as a stop, frameshift, or splice-site disruption that would trigger nonsense-mediated decay or abolish protein function, so it does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 compares the amino acid change to a previously established pathogenic variant at the same residue. Because this variant does not change the amino acid (p.Ile140=), there is no altered residue to compare.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: insufficient evidence was available. No proband or parental (maternity and paternity) genotype data were available to determine whether the variant arose de novo.
PS3	Not assessed	Not assessed: insufficient evidence was available; no functional assay results could be evaluated for this variant.
PS4	Not met	Not met: no case-control or variant-specific case data show enrichment of this variant in affected individuals. Instead, it is common in general-population databases (up to about 1.5% in African/African American individuals), which argues against a pathogenic role.	PMID:25741868 gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: PM1 concerns missense variants in mutational hotspots or critical functional domains. This synonymous change alters no amino acid, so there is no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Not met	Not met: the variant is not rare. It appears in gnomAD at overall frequencies of about 0.09-0.18%, with a maximum population frequency of about 1.5% (African/African American) and multiple homozygotes - consistent with a common polymorphism (rs3856746) rather than a rare disease allele.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
PM3	N/A	Not applicable: PM3 applies only to recessive disorders. CTNNB1 syndrome is an autosomal dominant neurodevelopmental disorder, so this criterion does not apply.	PMID:25741868 generic_acmg_combination_rules pvs1_gene_context clinvar
PM4	N/A	Not applicable: PM4 applies to changes in protein length (in-frame insertions/deletions or stop-loss). This synonymous variant leaves the protein length unchanged.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a novel missense change at a residue where a different missense change is already pathogenic. This variant changes no amino acid.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: insufficient evidence was available; no parental testing data were available to support an assumed de novo occurrence.
PP1	Not assessed	Not assessed: insufficient evidence was available; no family genotyping or segregation data were reported. Absence of data is not evidence for or against segregation.
PP2	N/A	Not applicable: PP2 concerns missense variants in genes with a low rate of benign missense variation. This is a synonymous change, so the criterion does not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: no computational evidence indicates a deleterious effect. SpliceAI predicts no significant splicing impact (max delta 0.13, below the 0.2 threshold), and missense predictors do not apply to a synonymous change.	spliceai PMID:25741868 generic_acmg_combination_rules
PP4	Not assessed	Not assessed: insufficient evidence was available; no phenotype description or family history was available to evaluate whether the variant fits a CTNNB1-related presentation.	PMID:25741868
PP5	Not met	Not met: no expert-panel classification labels this variant pathogenic. ClinVar lists it as Benign based on four laboratory submissions - the opposite direction - so PP5 is not met.	clinvar PMID:25741868
BA1	Met	Met (stand-alone benign): the variant is a common polymorphism. Its maximum population allele frequency is about 1.5% (African/African American in gnomAD v2.1 and v4.1), far above the 1% threshold expected for a severe, early-onset, predominantly de novo dominant disorder, so it cannot be a common cause of CTNNB1 syndrome.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS1	Met	Met (strong benign): the allele frequency (up to about 1.5% in African/African American populations) far exceeds what is expected for CTNNB1 syndrome, a severe, fully penetrant, predominantly de novo disorder. Observed homozygotes (8 in gnomAD v2.1, 17 in v4.1) are incompatible with a fully penetrant dominant disease allele.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS2	Not met	Not met: although homozygotes are present in gnomAD, that database does not provide phenotype-verified healthy-adult carrier status, which BS2 requires.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS3	Not assessed	Not assessed: insufficient evidence was available; no well-established functional studies showing no damaging effect could be evaluated.
BS4	Not assessed	Not assessed: insufficient evidence was available; no family members were genotyped, so lack of segregation could not be demonstrated.
BP1	N/A	Not applicable: BP1 applies to missense variants in genes where truncating variants cause disease. This is a synonymous change, so the criterion does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: insufficient evidence was available; no phase (trans/cis) or co-occurrence observations with a pathogenic variant were reported.	PMID:25741868 generic_acmg_combination_rules pvs1_gene_context clinvar
BP3	N/A	Not applicable: BP3 applies to in-frame insertions or deletions in repetitive regions. This synonymous variant does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: BP4 requires multiple independent computational lines predicting no impact. Only the SpliceAI no-impact prediction is available, and it is already used for BP7, so applying it again would double-count a single line of evidence.	spliceai PMID:25741868 generic_acmg_combination_rules
BP5	Not assessed	Not assessed: insufficient evidence was available; no alternate molecular basis of disease (for example, a co-occurring pathogenic variant) was reported for the case.	PMID:25741868
BP6	Not met	Not met: BP6 requires an expert-panel benign classification for this exact variant. Only ordinary laboratory submissions are available, which do not meet the criterion.	clinvar PMID:25741868
BP7	Met	Met (supporting): the variant is synonymous (p.Ile140=) and splice-prediction tools indicate no effect on splicing (SpliceAI max delta 0.13, below the 0.2 threshold), with the change located deep within exon 4, away from splice consensus sites.	spliceai PMID:25741868 generic_acmg_combination_rules

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