CTNNB1 c.1694G>A, p.Arg565His
NM_001904.4:c.1694G>A
COSMIC ID: COSM6981900
Variant of Uncertain Significance (VUS)
This CTNNB1 R565H missense variant is extremely rare (PM2) and computationally predicted benign (BP4) with missense not a known disease mechanism in CTNNB1 (BP1). No strong pathogenic evidence is available. Conflicting moderate pathogenic and supporting benign evidence leads to a final classification of VUS.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
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.1694G>A
Protein Change
R565H
Location
Exon 11
(Exon 11 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 565 in gene CTNNB1
Alternate Identifiers
COSM6981900
Variant interpretation based on transcript NM_001904.4
Genome Browser
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HGVS InputNM_001904:c.1694G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00279%
Rare
Highest in Population
European (non-Finnish)
0.00529%
Rare
Global: 0.00279%
European (non-Finnish): 0.00529%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251204Alt: 7Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00279%, 7/251204 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00529%, 6/113514 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 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
No evidence of other pathogenic variants at position 565 in gene CTNNB1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.524
0.524
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dprimateai: D
Benign:
CADD: 6.22metalr: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
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)". The evidence for this variant shows: it is a missense change (R565H), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant at R565H. Therefore, this criterion is not applied.
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 confirmation data. Therefore, this criterion is not applied.
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.
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. Therefore, this criterion is not applied.
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: R565 is not reported as a mutational hotspot or critical domain residue. Therefore, this criterion is not applied.
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: MAF = 0.00279% in gnomAD, extremely rare. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in 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: CTNNB1‐related disease is dominant and no trans data. Therefore, this criterion is not applied.
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 variant, no protein length change. Therefore, this criterion is not applied.
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 missense change has been seen as pathogenic." The evidence for this variant shows: no other pathogenic missense at residue R565. Therefore, this criterion is not applied.
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.
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 segregation data. Therefore, this criterion is not applied.
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 pathogenic mechanism is haploinsufficiency (LoF), not missense. Therefore, this criterion is not applied.
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." The evidence for this variant shows: in silico predictions are mixed, with benign predictions prevailing. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
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: ClinVar reports VUS only. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (stand‐alone benign)." The evidence for this variant shows: MAF = 0.00279%, well below >5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder (strong benign)." The evidence for this variant shows: frequency is very low. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." The evidence for this variant shows: no confirmed healthy adult carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well‐established functional studies show no damaging effect." 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 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.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss‐of‐function causes disease (supporting benign)." The evidence for this variant shows: CTNNB1 pathogenic mechanism is haploinsufficiency (LoF), and missense is not a known mechanism. Therefore, this criterion is applied at Supporting strength because missense substitutions are not a known disease mechanism for CTNNB1.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans/cis with a pathogenic variant for dominant disorders (supporting benign)." The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
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 change, not an in‐frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (supporting benign)." The evidence for this variant shows: mixed in silico predictions with overall benign outcome and SpliceAI score 0.09 suggesting no splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence predominantly indicates no functional 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 such case data. Therefore, this criterion is not applied.
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: no report of benign by reputable source. Therefore, this criterion is not applied.
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 not synonymous. Therefore, this criterion is not applied.