10-66280567-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013266.4(CTNNA3):c.1787G>A(p.Ser596Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,606,400 control chromosomes in the GnomAD database, including 122,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S596T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.47 ( 18019 hom., cov: 32)

Exomes 𝑓: 0.37 ( 104126 hom. )

Consequence

CTNNA3
NM_013266.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.986

Publications

43 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.454127E-6).

BP6

Variant 10-66280567-C-T is Benign according to our data. Variant chr10-66280567-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1169338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013266.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.1787G>A	p.Ser596Asn	missense	Exon 13 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.1787G>A	p.Ser596Asn	missense	Exon 13 of 18	NP_001120856.1	Q9UI47-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.1787G>A	p.Ser596Asn	missense	Exon 13 of 18	ENSP00000389714.1	Q9UI47-1
CTNNA3	ENST00000682758.1		c.1787G>A	p.Ser596Asn	missense	Exon 14 of 19	ENSP00000508047.1	Q9UI47-1
CTNNA3	ENST00000684154.1		c.1787G>A	p.Ser596Asn	missense	Exon 13 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

70958

AN:

151630

Hom.:

17989

Cov.:

show subpopulations

Gnomad AFR

AF:

0.679

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.421

Gnomad ASJ

AF:

0.391

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.389

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.370

Gnomad OTH

AF:

0.466

GnomAD2 exomes

AF:

0.404

AC:

99984

AN:

247298

AF XY:

0.398

show subpopulations

Gnomad AFR exome

AF:

0.677

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.393

Gnomad EAS exome

AF:

0.433

Gnomad FIN exome

AF:

0.434

Gnomad NFE exome

AF:

0.365

Gnomad OTH exome

AF:

0.388

GnomAD4 exome

AF:

0.372

AC:

541384

AN:

1454652

Hom.:

104126

Cov.:

AF XY:

0.371

AC XY:

268575

AN XY:

723780

show subpopulations

African (AFR)

AF:

0.686

AC:

22633

AN:

32980

American (AMR)

AF:

0.410

AC:

18065

AN:

44082

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

9959

AN:

25990

East Asian (EAS)

AF:

0.445

AC:

17522

AN:

39380

South Asian (SAS)

AF:

0.371

AC:

31786

AN:

85590

European-Finnish (FIN)

AF:

0.432

AC:

22825

AN:

52790

Middle Eastern (MID)

AF:

0.346

AC:

1970

AN:

5694

European-Non Finnish (NFE)

AF:

0.355

AC:

393336

AN:

1108048

Other (OTH)

AF:

0.388

AC:

23288

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

15405

30811

46216

61622

77027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12606

25212

37818

50424

63030

<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:

0.468

AC:

71039

AN:

151748

Hom.:

18019

Cov.:

AF XY:

0.467

AC XY:

34582

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.679

AC:

28113

AN:

41406

American (AMR)

AF:

0.420

AC:

6388

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

1354

AN:

3464

East Asian (EAS)

AF:

0.448

AC:

2304

AN:

5140

South Asian (SAS)

AF:

0.387

AC:

1865

AN:

4814

European-Finnish (FIN)

AF:

0.435

AC:

4589

AN:

10546

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.370

AC:

25111

AN:

67876

Other (OTH)

AF:

0.464

AC:

973

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1791

3582

5374

7165

8956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.394

Hom.:

54528

Bravo

AF:

0.475

TwinsUK

AF:

0.346

AC:

1282

ALSPAC

AF:

0.338

AC:

1304

ESP6500AA

AF:

0.670

AC:

2954

ESP6500EA

AF:

0.362

AC:

3114

ExAC

AF:

0.411

AC:

49943

Asia WGS

AF:

0.443

AC:

1535

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Arrhythmogenic right ventricular dysplasia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.4

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.044

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0000074

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

PhyloP100

0.99

PrimateAI

Benign

0.48

PROVEAN

Benign

2.0

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.028

MPC

0.021

ClinPred

0.0013

GERP RS

3.2

Varity_R

0.029

gMVP

0.086

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over