3-41235763-G-C

Position:

• chr3-41235763-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Moderate

The ENST00000349496.11(CTNNB1):​c.1723G>C​(p.Gly575Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 ENST00000349496.11 missense
• Clinical Significance: Not reported in ClinVar
• 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 Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript ENST00000349496.11 (CTNNB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 208674
• PM1: In a helix (size 14) in uniprot entity CTNB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000349496.11
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNB1. . Gene score misZ 3.846 (greater than the threshold 3.09). Trascript score misZ 5.712 (greater than threshold 3.09). GenCC has associacion of gene with severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.1723G>C	p.Gly575Arg	missense_variant	11/15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1723G>C	p.Gly575Arg	missense_variant	11/15	1	NM_001904.4	ENSP00000344456	P4

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;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	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;D;.;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	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	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.8	.;.;.;D;.;.;.;.;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	.;.;.;D;.;.;.;.;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	.;.;.;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		0.98, 0.98, 0.98, 0.98
MutPred		0.60		Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;.;.;.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);.;.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-41277254;