chr3-41224526-C-T

Variant names:

• chr3-41224526-C-T
• rs1448779783
• NM_001904.4:c.14C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001904.4(CTNNB1):​c.14C>T​(p.Ala5Val) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense, splice_region
• Scores: Splicing: ADA: 0.9923
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.14C>T	p.Ala5Val	missense_variant, splice_region_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.14C>T	p.Ala5Val	missense_variant, splice_region_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.14C>T	p.Ala5Val	missense_variant, splice_region_variant	Exon 3 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.14C>T		splice_region_variant, 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	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	0.053
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.59	.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;D;D;.;D;.;.;.;D;.;.;.;.;.;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	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	0.90	L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;.;.;L;.;L;L;L;.;L;L;L;L;L;L
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.66	.;.;N;.;D;.;N;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N
REVEL	Benign	0.19
Sift	Uncertain	0.023	.;.;D;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Benign	0.15	.;.;T;.;.;.;D;T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T
Polyphen		0.0010	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, 0.50, 0.56
MutPred		0.20		Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);Gain of catalytic residue at A5 (P = 0.0151);
MVP		0.72
MPC		1.1
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.081
gMVP		0.70
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
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: rs1448779783; hg19: chr3-41266017; COSMIC: COSV62698897;