11-57794016-C-T

Position:

chr11-57794016-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001085458.2(CTNND1):c.202C>T(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 1,613,848 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

CTNND1
NM_001085458.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 3.22

Variant links:

Genes affected

CTNND1 (HGNC:2515): (catenin delta 1) This gene encodes a member of the Armadillo protein family, which function in adhesion between cells and signal transduction. Multiple translation initiation codons and alternative splicing result in many different isoforms being translated. Not all of the full-length natures of the described transcript variants have been determined. Read-through transcription also exists between this gene and the neighboring upstream thioredoxin-related transmembrane protein 2 (TMX2) gene. [provided by RefSeq, Dec 2010]

CTNND1 links:

TMX2-CTNND1 (HGNC:):

TMX2-CTNND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000322 (49/152190) while in subpopulation NFE AF= 0.000529 (36/68014). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNND1	NM_001085458.2 linkuse as main transcript	c.202C>T	p.Arg68Trp	missense_variant	4/21	ENST00000399050.10
TMX2-CTNND1	NR_037646.1 linkuse as main transcript	n.761C>T		non_coding_transcript_exon_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNND1	ENST00000399050.10 linkuse as main transcript	c.202C>T	p.Arg68Trp	missense_variant	4/21	1	NM_001085458.2		O60716-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000385

AC:

AN:

246850

Hom.:

AF XY:

0.000417

AC XY:

AN XY:

134146

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.000687

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000586

AC:

857

AN:

1461658

Hom.:

Cov.:

AF XY:

0.000567

AC XY:

412

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.000707

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000322

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000440

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00110

AC:

ExAC

AF:

0.000414

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2022

The c.202C>T (p.R68W) alteration is located in exon 4 (coding exon 2) of the CTNND1 gene. This alteration results from a C to T substitution at nucleotide position 202, causing the arginine (R) at amino acid position 68 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CTNND1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.027

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

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.8

L;.;L;.;L;L;L;L;.;.;.;L;.;.;.;.;L;.

MutationTaster

Benign

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;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0080

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.045

D;D;D;T;D;D;D;D;T;T;T;D;T;T;T;T;D;D

Polyphen

1.0

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

Vest4

0.39

MVP

0.82

MPC

1.0

ClinPred

0.84

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.44

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over