10-66766413-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_013266.4(CTNNA3):c.1132C>T(p.Arg378Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000607 in 1,602,088 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 1 hom. )

Consequence

CTNNA3
NM_013266.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.99

Publications

7 publications found

Variant links:

Genes affected

CTNNA3 (HGNC:2511): (catenin alpha 3) This gene encodes a protein that belongs to the vinculin/alpha-catenin family. The encoded protein plays a role in cell-cell adhesion in muscle cells. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia, familial 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

CTNNA3 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 13
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital heart disease
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

CTNNA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 10-66766413-G-A is Benign according to our data. Variant chr10-66766413-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409017.

BS2

High AC in GnomAd4 at 67 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA3	NM_013266.4 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 9 of 18	ENST00000433211.7	NP_037398.2	Q9UI47-1A8K141

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA3	ENST00000433211.7 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 9 of 18	1	NM_013266.4	ENSP00000389714.1		Q9UI47-1

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000756

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000469

AC:

114

AN:

242920

AF XY:

0.000504

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000181

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000222

Gnomad FIN exome

AF:

0.000516

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.000511

GnomAD4 exome

AF:

0.000625

AC:

906

AN:

1449968

Hom.:

Cov.:

AF XY:

0.000626

AC XY:

451

AN XY:

720494

show subpopulations

African (AFR)

AF:

0.0000606

AC:

AN:

33004

American (AMR)

AF:

0.000347

AC:

AN:

43182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25680

East Asian (EAS)

AF:

0.000126

AC:

AN:

39582

South Asian (SAS)

AF:

0.000215

AC:

AN:

83544

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

53004

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000732

AC:

810

AN:

1106396

Other (OTH)

AF:

0.000501

AC:

AN:

59874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000440

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41504

American (AMR)

AF:

0.000262

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.000756

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000525

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000453

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 25741868) -

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Jul 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1132C>T (p.R378C) alteration is located in exon 9 (coding exon 8) of the CTNNA3 gene. This alteration results from a C to T substitution at nucleotide position 1132, causing the arginine (R) at amino acid position 378 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Jul 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CTNNA3 c.1132C>T (p.Arg378Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 242920 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 115 fold of the estimated maximal expected allele frequency for a pathogenic variant in CTNNA3 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06). To our knowledge, no occurrence of c.1132C>T in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 409017). Based on the evidence outlined above, the variant was classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 13

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CTNNA3-related disorder

Benign:1

Mar 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Benign

0.18

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.1

PhyloP100

4.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.4

REVEL

Benign

0.27

Sift

Benign

0.099

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.90

MVP

0.73

MPC

0.18

ClinPred

0.11

GERP RS

6.2

Varity_R

0.22

gMVP

0.42

Mutation Taster

=96/4

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over