CTNNB1 c.1155C>A, p.Leu385=
NM_001904.4:c.1155C>A
COSMIC ID: COSM10478999
Likely Benign
This synonymous CTNNB1 variant shows no amino acid change or splicing impact, is rare in population databases, and is reported as benign in ClinVar. Application of one moderate (PM2) and three supporting benign criteria (BP4, BP6, BP7) leads to a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
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.1155C>A
Protein Change
L385=
Location
Exon 8
(Exon 8 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM10478999
Variant interpretation based on transcript NM_001904.4
Genome Browser
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HGVS InputNM_001904:c.1155C>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0403%
Low Frequency
Highest in Population
East Asian
0.431%
Common
Global: 0.0403%
East Asian: 0.431%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282732Alt: 114Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0403%, 114/282732 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.431%, 86/19948 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
2 LB
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (2 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.37
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 (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: NM_001904.4:c.1155C>A is a synonymous variant (L385=), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the rule for null variants.
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: L385= does not change the amino acid. Therefore, this criterion is not applied because there is no amino acid change.
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 data on de novo occurrence or parental testing. Therefore, this criterion is not applied because de novo status cannot be evaluated without parental data.
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 not available.
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 cohort data. Therefore, this criterion is not applied because case prevalence data are not available.
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: c.1155C>A lies in a region without known mutational hot spot or domain annotation. Therefore, this criterion is not applied because the variant is not within a recognized hot spot or domain.
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: present in gnomAD at MAF=0.0403% overall and absent in homozygotes, which is below the 0.1% threshold. Therefore, this criterion is applied at Moderate strength because the allele frequency is extremely low in population databases.
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 other variants. Therefore, this criterion is not applied because phasing data are not available.
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: synonymous change with no change in protein length. Therefore, this criterion is not applied because there is no protein length alteration.
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 amino acid change. 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 information. Therefore, this criterion is not applied because de novo status is unevaluable without any parental data.
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 because family segregation information is not available.
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: synonymous variant, 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: CADD score 0.37 and SpliceAI score 0 predict no deleterious effect. Therefore, this criterion is not applied because computational evidence does not 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 phenotype or clinical information provided. Therefore, this criterion is not applied because phenotype data are not available.
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 benign/likely benign only. 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". The evidence for this variant shows: MAF=0.0403%, which is below typical BA1 thresholds (e.g., >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". The evidence for this variant shows: MAF is low (0.0403%) and does not exceed disorder-specific thresholds. Therefore, this criterion is not applied.
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 confirmed healthy adult homozygotes or phenotyped individuals. 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 on protein function or splicing". The evidence for this variant shows: no functional assays performed. 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 family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: synonymous change, not missense. Therefore, this criterion is not applied.
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 phase 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 indels in repetitive region without known function". The evidence for this variant shows: not an 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". The evidence for this variant shows: CADD score 0.37 and SpliceAI score 0 predict no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational tools predict 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 case reports with alternate diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
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: ClinVar entries report benign (3 labs) and likely benign (2 labs) without underlying data. Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as benign without available primary evidence.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and no conservation at the nucleotide level". The evidence for this variant shows: L385= is synonymous and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because it is a synonymous change without splicing impact.