rs187752783

Variant names:

• chr10-66766413-G-A
• rs187752783
• NM_013266.4:c.1132C>T
• CTNNA3 p.Arg378Cys

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.99
• Publications: 7 publications found

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

ACMG classification

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 Unknown,AD gene.

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.1132C>T	p.Arg378Cys	missense	Exon 9 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.1132C>T	p.Arg378Cys	missense	Exon 9 of 18	NP_001120856.1	Q9UI47-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.1132C>T	p.Arg378Cys	missense	Exon 9 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.1132C>T	p.Arg378Cys	missense	Exon 10 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.1132C>T	p.Arg378Cys	missense	Exon 9 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 152006 Hom.: 0 Cov.: 32

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

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.: 1 Cov.: 31 AF XY: 0.000626 AC XY: 451 AN XY: 720494

African (AFR) AF: 0.0000606 AC: 2 AN: 33004

American (AMR) AF: 0.000347 AC: 15 AN: 43182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39582

South Asian (SAS) AF: 0.000215 AC: 18 AN: 83544

European-Finnish (FIN) AF: 0.000472 AC: 25 AN: 53004

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.000732 AC: 810 AN: 1106396

Other (OTH) AF: 0.000501 AC: 30 AN: 59874

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000498 AC XY: 37 AN XY: 74356

African (AFR) AF: 0.0000482 AC: 2 AN: 41504

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.000756 AC: 8 AN: 10580

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000525 Hom.: 1

Bravo AF: 0.000332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	not specified (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 13 (1)
-	-	1	CTNNA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.27
Sift	Benign	0.099	T
Sift4G	Benign	0.23	T
Varity_R		0.22
gMVP		0.42
Mutation Taster		=96/4	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs187752783;

hg19: chr10-68526171;

COSMIC: COSV65593446;