CTNNB1 c.2246C>A, p.Pro749Gln
NM_001904.4:c.2246C>A
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
0.329
Uncertain (Low)
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
CTNNB1
Transcript
NM_001904.4
MANE Select
Total Exons
15
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001904.3 | Alternative | 15 exons | Forward |
Variant Details
HGVS Notation
NM_001904.4:c.2246C>A
Protein Change
P749Q
Location
Exon 15
(Exon 15 of 15)
5'
Exon Structure (15 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 749 in gene CTNNB1
Variant interpretation based on transcript NM_001904.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
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
No evidence of other pathogenic variants at position 749 in gene CTNNB1
Functional Studies
Summary
The CTNNB1 P749Q variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.329
0.329
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
primateai: D
Benign:
CADD: 4.22
polyphen_prediction: benign
metasvm: T
metalr: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "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 missense change (P749Q), not a null variant. 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 for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: there is no previously established pathogenic variant resulting in P749Q. Therefore, this criterion is not applied because there is no known pathogenic variant at this residue.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "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 status or parental testing data are available. Therefore, this criterion is not applied because de novo confirmation is lacking.
PS3
PS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "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 missing.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or affected individual data are available. Therefore, this criterion is not applied because prevalence in cases is not documented.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no evidence that position 749 falls within a defined mutational hotspot or critical domain unique for CTNNB1. Therefore, this criterion is not applied because hotspot/domain data are lacking.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is not found in population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on trans configuration with another variant. Therefore, this criterion is not applied because trans-phase information is unavailable.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a missense change without alteration of protein length. Therefore, this criterion is not applied because there is no protein length change.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense changes at residue 749 have been reported. Therefore, this criterion is not applied because no other pathogenic variant exists at this residue.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied because de novo status is unconfirmed.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because segregation information is lacking.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "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: CTNNB1 has both pathogenic missense and loss-of-function mechanisms; no specific constraint data provided. Therefore, this criterion is not applied due to insufficient gene-specific missense constraint information.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "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 predictions are mixed, with majority benign and SpliceAI score 0.01. Therefore, this criterion is not applied because computational evidence does not predominantly support a deleterious effect.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no patient phenotype or clinical information. Therefore, this criterion is not applied because phenotype data are unavailable.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied because no reputable source reports it as pathogenic.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied because frequency is not high.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied because frequency is not greater than expected.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no observation in healthy individuals. Therefore, this criterion is not applied due to lack of healthy individual data.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "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 because functional assays are absent.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied because segregation information is unavailable.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: CTNNB1 has both LoF and missense pathogenic variants reported. Therefore, this criterion is not applied because missense variants can be pathogenic in CTNNB1.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on allelic configuration with other variants. Therefore, this criterion is not applied because configuration data are unavailable.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense variant, not an in-frame indel. Therefore, this criterion is not applied because it is not an in-frame indel.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: majority of in silico tools predict benign effect (CADD, PolyPhen-2, MetaSVM, MetaLR), REVEL score 0.33, and SpliceAI score 0.01. Therefore, this criterion is applied at Supporting strength because computational data suggest no impact.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports or alternate molecular findings. Therefore, this criterion is not applied because no case context is available.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other reputable sources. Therefore, this criterion is not applied because no such reports exist.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied because it is not a synonymous variant.