3-41224546-A-G

Variant names:

• chr3-41224546-A-G
• NM_001904.4:c.34A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001904.4(CTNNB1):​c.34A>G​(p.Met12Val) 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 U:1
• Conservation: PhyloP100: 9.32

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3699146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.34A>G	p.Met12Val	missense_variant	Exon 3 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.34A>G	p.Met12Val	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.34A>G	p.Met12Val	missense_variant	Exon 3 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.34A>G		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000520353.1

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

Submissions by phenotype

not provided Uncertain:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the CTNNB1 protein (p.Met12Val). 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	0.094
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Uncertain	0.42	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	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.37	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	-1.0	T
MutationAssessor	Benign	0.14	N;.;N;.;N;N;N;N;N;.;N;N;.;.;N;N;N;.;.;.;.;N;N;.;.;.;N;.;.;N;N;.;N;.;N;.;N;N;N;N;N
PhyloP100		9.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.92	.;N;.;.;N;.;D;.;N;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	.;D;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T
Sift4G	Pathogenic	0.0	.;D;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T
Polyphen		0.0030	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		0.62, 0.61, 0.61, 0.68, 0.64
MutPred		0.31		Loss of disorder (P = 0.0317);.;Loss of disorder (P = 0.0317);.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);.;.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);.;.;.;.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);.;Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);Loss of disorder (P = 0.0317);
MVP		0.94
MPC		1.1
ClinPred		0.50	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
gMVP		0.77
Mutation Taster		=22/78	disease causing

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

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Other links and lift over

hg19: chr3-41266037;