Genetic Variant CTNNB1:p.Met1? (chr3-41224069-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001904.4(CTNNB1):c.1A>T(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.000000684 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CTNNB1
NM_001904.4 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.46

Publications

0 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)

CTNNB1 links:

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ACMG classification

Classification was made for transcript

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 8 codons. Genomic position: 41224534. Lost 0.009 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 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 15	ENST00000349496.11	NP_001895.1	P35222A0A024R2Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTNNB1	ENST00000349496.11 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 15	1	NM_001904.4	ENSP00000344456.5	P35222
CTNNB1	ENST00000645982.1 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 16			ENSP00000494845.1	P35222
CTNNB1	ENST00000715152.1 link	n.1A>T		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251376

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111750

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Benign

0.95

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

0.076

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

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

-0.93

PhyloP100

5.5

PROVEAN

Benign

-0.53

.;.;N;.;D;.;N;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

.;.;D;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

Sift4G

Benign

0.57

.;.;T;.;.;.;T;T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;D

Polyphen

0.0060

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

0.88, 0.88, 0.88, 0.87

MutPred

0.97

Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);

MVP

0.92

ClinPred

0.59

GERP RS

5.6

Varity_R

0.81

gMVP

0.64

Mutation Taster

=51/149

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over