rs121913395

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001904.4(CTNNB1):​c.61G>A​(p.Ala21Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00
Variant links:
Genes affected
CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the CTNNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 3.846 (above the threshold of 3.09). Trascript score misZ: 5.712 (above the threshold of 3.09). GenCC associations: The gene is linked to severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.
BP4
Computational evidence support a benign effect (MetaRNN=0.26455465).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTNNB1NM_001904.4 linkc.61G>A p.Ala21Thr missense_variant Exon 3 of 15 ENST00000349496.11 NP_001895.1 P35222A0A024R2Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTNNB1ENST00000349496.11 linkc.61G>A p.Ala21Thr missense_variant Exon 3 of 15 1 NM_001904.4 ENSP00000344456.5 P35222
CTNNB1ENST00000645982.1 linkc.61G>A p.Ala21Thr missense_variant Exon 3 of 16 ENSP00000494845.1 P35222

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CTNNB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 21 of the CTNNB1 protein (p.Ala21Thr). ClinVar contains an entry for this variant (Variation ID: 376224). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.063
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;T;T;.;T;T;T;T;T;T;T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.26
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;N;.;N;N;N;N;N;.;N;N;.;.;N;N;N;.;.;.;.;N;N;.;.;.;N;.;.;N;N;.;N;.;N;.;N;N;N;N;N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
0.45
.;N;.;.;N;.;.;.;N;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N
REVEL
Benign
0.15
Sift
Benign
0.098
.;T;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T
Sift4G
Benign
0.14
.;T;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T
Polyphen
0.036
B;.;B;.;B;B;B;B;B;.;B;B;.;.;B;B;B;.;.;.;.;B;B;.;.;.;B;.;.;B;B;.;B;.;B;.;B;B;B;B;B
Vest4
0.49, 0.48, 0.49, 0.49, 0.48
MutPred
0.25
Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;.;.;.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);
MVP
0.61
MPC
1.1
ClinPred
0.65
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.15
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913395; hg19: chr3-41266064; COSMIC: COSV62699844; COSMIC: COSV62699844; API