3-41224536-G-A

Variant names:

• chr3-41224536-G-A
• rs2125616674
• NM_001904.4:c.24G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001330729.2(CTNNB1):​c.3G>A​(p.Met1?) variant causes a start lost 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001330729.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 5 codons. Genomic position: 41224546. Lost 0.006 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.24G>A	p.Met8Ile	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.24G>A	p.Met8Ile	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.24G>A	p.Met8Ile	missense_variant	Exon 3 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.24G>A		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

Jul 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	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	Uncertain	0.24
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T;D;T;D;T;T;T;T;T;D;T;T;D;D;T;T;T;D;D;D;D;T;T;T;T;T;T;D;T;T;T;D;T;T;T;D;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	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		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	.;N;.;.;N;.;D;.;N;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;.;.;T;.;.;.;D;.;T;T;.;.;T;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;D
Polyphen		0.0020	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		0.65, 0.66, 0.64, 0.68, 0.87
MutPred		0.26		Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;.;.;.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);
MVP		0.93
MPC		1.2
ClinPred		0.87	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.53
Mutation Taster		=25/175	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs2125616674; hg19: chr3-41266027; COSMIC: COSV62724983;