3-41224645-T-C

Variant names:

• chr3-41224645-T-C
• rs121913407
• NM_001904.4:c.133T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001904.4(CTNNB1):​c.133T>C​(p.Ser45Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S45F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3 O:1
• Conservation: PhyloP100: 8.02
• Publications: 406 publications found

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]

CTNNB1 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• severe intellectual disability-progressive spastic diplegia syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• exudative vitreoretinopathy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001904.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-41224646-C-T is described in ClinVar as Pathogenic|other. ClinVar VariationId is 17588.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 3-41224645-T-C is Pathogenic according to our data. Variant chr3-41224645-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17589.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.133T>C	p.Ser45Pro	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.133T>C	p.Ser45Pro	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.133T>C	p.Ser45Pro	missense_variant	Exon 3 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.133T>C		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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:2

-

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

-

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hepatocellular carcinoma Pathogenic:1

Jul 08, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	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	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.65	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	-0.52	T
MutationAssessor	Uncertain	2.2	M;.;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL	Uncertain	0.34
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		0.99	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		0.77, 0.77, 0.77, 0.77
MutPred		0.23		Loss of phosphorylation at S45 (P = 0.0334);.;Loss of phosphorylation at S45 (P = 0.0334);.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);.;.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);.;.;.;.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);.;Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);Loss of phosphorylation at S45 (P = 0.0334);
MVP		0.87
MPC		2.5
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913407; hg19: chr3-41266136; COSMIC: COSV62687880; COSMIC: COSV62687880;