rs121913395

Positions:

• chr3-41224573-G-A
• chr3-41224573-G-C
• chr3-41224573-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNB1. . Gene score misZ 3.846 (greater than the threshold 3.09). Trascript score misZ 5.712 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.61G>A	p.Ala21Thr	missense_variant	3/15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.61G>A	p.Ala21Thr	missense_variant	3/15	1	NM_001904.4	ENSP00000344456	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2023

ClinVar contains an entry for this variant (Variation ID: 376224). 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CTNNB1-related conditions. 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. 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. -

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
MutationTaster	Benign	1.0	D;D;D;D;D
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

Other links and lift over

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