dbSNP rs748653573: CTNNB1:p.Arg710Ser (chr3-41238067-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM5PP2BP4_ModerateBS2

The NM_001904.4(CTNNB1):c.2128C>A(p.Arg710Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R710C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CTNNB1
NM_001904.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.64

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-41238067-C-T is described in Lovd as [Likely_pathogenic].

PP2

Missense variant in the CTNNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 3.846 (above the threshold of 3.09). Trascript score misZ: 5.712 (above the threshold of 3.09). GenCC associations: The gene is linked to severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.

BP4

Computational evidence support a benign effect (MetaRNN=0.19088176).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4 link	c.2128C>A	p.Arg710Ser	missense_variant	Exon 14 of 15	ENST00000349496.11	NP_001895.1	P35222A0A024R2Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11 link	c.2128C>A	p.Arg710Ser	missense_variant	Exon 14 of 15	1	NM_001904.4	ENSP00000344456.5		P35222
CTNNB1	ENST00000645982.1 link	c.2128C>A	p.Arg710Ser	missense_variant	Exon 14 of 16			ENSP00000494845.1		P35222

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251354

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135846

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 SAS 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:

0.00000616

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.31

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

-0.19

Eigen_PC

Benign

0.033

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.19

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

-1.1

MutationAssessor

Benign

0.29

N;N;.;N;N;N;N;N;.;N;N;.;.;N;N;N;.;.;.;.;N;N;.;.;N;.;.;N;N;.;N;.;N;.;N;N;N;N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.47

.;.;.;N;.;.;.;.;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.76

.;.;.;T;.;.;.;.;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.76

.;.;.;T;.;.;.;.;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

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

0.91, 0.92, 0.91, 0.90, 0.91

MutPred

0.38

Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;.;.;.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;.;Loss of catalytic residue at R710 (P = 0.0082);.;.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);

MVP

0.88

MPC

0.25

ClinPred

0.43

GERP RS

5.2

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.37

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over