3-41224555-G-A

Position:

• chr3-41224555-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001904.4(CTNNB1):​c.43G>A​(p.Glu15Lys) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E15D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided 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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001904.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CTNNB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.325251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNB1	NM_001904.4	c.43G>A	p.Glu15Lys	missense_variant	3/15	ENST00000349496.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNB1	ENST00000349496.11	c.43G>A	p.Glu15Lys	missense_variant	3/15	1	NM_001904.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Severe intellectual disability-progressive spastic diplegia syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Dec 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.33	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	0.067
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.33	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	0.42	N;.;N;.;N;N;N;N;N;.;N;N;.;.;N;N;N;.;.;.;.;N;N;.;.;.;N;.;.;N;N;.;N;.;N;.;N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
Polyphen		0.11	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		0.66, 0.66, 0.65, 0.65, 0.67
MutPred		0.31		Gain of ubiquitination at E15 (P = 0.0185);.;Gain of ubiquitination at E15 (P = 0.0185);.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);.;.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);.;.;.;.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);.;Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);Gain of ubiquitination at E15 (P = 0.0185);
MVP		0.76
MPC		1.3
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.81

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: rs1575315288; hg19: chr3-41266046; COSMIC: COSV62704285; COSMIC: COSV62704285;