dbSNP rs765655737: CTNND2:p.Pro268Leu (chr5-11385039-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001332.4(CTNND2):c.803C>T(p.Pro268Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000034 in 1,177,376 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P268Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CTNND2
NM_001332.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.15

Publications

0 publications found

Variant links:

Genes affected

CTNND2 (HGNC:2516): (catenin delta 2) This gene encodes an adhesive junction associated protein of the armadillo/beta-catenin superfamily and is implicated in brain and eye development and cancer formation. The protein encoded by this gene promotes the disruption of E-cadherin based adherens junction to favor cell spreading upon stimulation by hepatocyte growth factor. This gene is overexpressed in prostate adenocarcinomas and is associated with decreased expression of tumor suppressor E-cadherin in this tissue. This gene resides in a region of the short arm of chromosome 5 that is deleted in Cri du Chat syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

CTNND2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Illumina
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
benign adult familial myoclonic epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CTNND2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNND2	NM_001332.4 link	c.803C>T	p.Pro268Leu	missense_variant	Exon 7 of 22	ENST00000304623.13	NP_001323.1	Q9UQB3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNND2	ENST00000304623.13 link	c.803C>T	p.Pro268Leu	missense_variant	Exon 7 of 22	1	NM_001332.4	ENSP00000307134.8		Q9UQB3-1

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000291

AC:

AN:

1029396

Hom.:

Cov.:

AF XY:

0.00000408

AC XY:

AN XY:

489670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20718

American (AMR)

AF:

0.00

AC:

AN:

6362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11334

East Asian (EAS)

AF:

0.00

AC:

AN:

20254

South Asian (SAS)

AF:

0.00

AC:

AN:

19326

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2602

European-Non Finnish (NFE)

AF:

0.00000337

AC:

AN:

891170

Other (OTH)

AF:

0.00

AC:

AN:

39370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.642

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40958

American (AMR)

AF:

0.00

AC:

AN:

14908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

5066

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66504

Other (OTH)

AF:

0.00

AC:

AN:

2030

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.65

T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

7.1

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0040

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.43

MutPred

0.27

Gain of stability (P = 0.047);.;.;

MVP

0.91

MPC

2.1

ClinPred

0.98

GERP RS

3.5

Varity_R

0.40

gMVP

0.60

Mutation Taster

=67/33

polymorphism

(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