NM_001904.4:c.122C>T

Variant names:

• chr3-41224634-C-T
• rs121913413
• NM_001904.4:c.122C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_001904.4(CTNNB1):​c.122C>T​(p.Thr41Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a modified_residue Phosphothreonine; by GSK3-beta (size 0) in uniprot entity CTNB1_HUMAN
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763
• PP5: Variant 3-41224634-C-T is Pathogenic according to our data. Variant chr3-41224634-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17587.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.122C>T	p.Thr41Ile	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.122C>T	p.Thr41Ile	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.122C>T	p.Thr41Ile	missense_variant	Exon 3 of 16			ENSP00000494845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Desmoid disease, hereditary Pathogenic:1

May 10, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A CTNNB1 c.122C>T (p.Thr41Ile) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals with desmoid-type fibromatosis, particularly pediatric cases (Trautmann M et al., PMID: 32099073; An J et al., PMID: 33914771) in addition to pilomatricomas (Akasaka E et al., PMID: 28651848; Chan EF et al., PMID: 10192393). It has also been reported in numerous different types of malignancies in the cancer database COSMIC (COSV62688008). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The CTNNB1 c.122C>T (p.Thr41Ile) variant resides within a Gsk3b phosphorylation site of the CTNNB1 gene that is defined as a critical region and constitutes a mutational hotspot (Trautmann M et al., PMID: 32099073). Functional studies show that the p.Thr41Ile variant is predicted to confer a gain of function to the CTNNB1 protein as demonstrated by nuclear accumulation of CTNNB1 in culture, indicating that this variant impacts protein function (Garcia-Rostan G et al., PMID: 10213482). Based on an internally developed protocol informed by the ACMG/AMP guidelines (18), and gene-specific practices from the ClinGen Criteria Specification Registry, the CTNNB1 c.122C>T (p.Thr41Ile) variant is classified as likely pathogenic. -

Pilomatrixoma Pathogenic:1

Apr 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;T;D;T;D;D;D;D;D;T;D;D;.;T;D;D;D;T;.;T;T;D;D;.;.;.;D;T;.;D;D;T;D;.;D;T;D;D;D;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.7	M;.;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Polyphen		1.0	D;.;D;.;D;D;D;D;D;.;D;D;.;.;D;D;D;.;.;.;.;D;D;.;.;.;D;.;.;D;D;.;D;.;D;.;D;D;D;D;D
Vest4		0.71, 0.72, 0.72, 0.73, 0.71
MutPred		0.35		Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;.;.;.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);
MVP		0.74
MPC		2.3
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.87
gMVP		0.86

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: rs121913413; hg19: chr3-41266125; COSMIC: COSV62688008; COSMIC: COSV62688008;