NM_001904.4:c.100G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1PM1PM2PM5PP3

The NM_001904.4(CTNNB1):​c.100G>C​(p.Gly34Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G34V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 missense

Scores

13
3
3

Clinical Significance

Likely pathogenic no assertion criteria provided P:10

Conservation

PhyloP100: 10.0

Publications

148 publications found
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS1
Transcript NM_001904.4 (CTNNB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376232
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 chr3-41224613-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17582.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTNNB1NM_001904.4 linkc.100G>C p.Gly34Arg missense_variant Exon 3 of 15 ENST00000349496.11 NP_001895.1 P35222A0A024R2Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTNNB1ENST00000349496.11 linkc.100G>C p.Gly34Arg missense_variant Exon 3 of 15 1 NM_001904.4 ENSP00000344456.5 P35222
CTNNB1ENST00000645982.1 linkc.100G>C p.Gly34Arg missense_variant Exon 3 of 16 ENSP00000494845.1 P35222
CTNNB1ENST00000715152.1 linkn.100G>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: Likely pathogenic
Submissions summary: Pathogenic:10
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Adrenal cortex carcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Pilomatrixoma Pathogenic:1
Jul 14, 2015
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Malignant neoplasm of body of uterus Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Gastric adenocarcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Lung adenocarcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Medulloblastoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Malignant melanoma of skin Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Craniopharyngioma Pathogenic:1
Jul 14, 2015
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Hepatocellular carcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Squamous cell carcinoma of the head and neck Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.90
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
0.97
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;D;.;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP
Benign
0.065
D
MetaRNN
Pathogenic
0.84
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
-0.37
T
MutationAssessor
Uncertain
2.7
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
10
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-8.0
.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL
Uncertain
0.60
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
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
0.85, 0.84, 0.85, 0.85, 0.89
MutPred
0.49
Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;.;.;.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);
MVP
0.81
MPC
2.5
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.94
gMVP
0.90
Mutation Taster
=13/87
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913399; hg19: chr3-41266103; COSMIC: COSV62687931; COSMIC: COSV62687931; API