rs190073606

Variant names:

• chr10-67219671-T-C
• rs190073606
• NM_013266.4:c.779A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_013266.4(CTNNA3):​c.779A>G​(p.Gln260Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. Q260H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.19
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005650878).
• BP6: Variant 10-67219671-T-C is Benign according to our data. Variant chr10-67219671-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474826.
• BS2: High AC in GnomAd4 at 41 AD,Unknown 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.779A>G	p.Gln260Arg	missense	Exon 6 of 18	NP_037398.2
	CTNNA3	NM_001127384.3		c.779A>G	p.Gln260Arg	missense	Exon 6 of 18	NP_001120856.1
	CTNNA3	NM_001291133.2		c.815A>G	p.Gln272Arg	missense	Exon 7 of 9	NP_001278062.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.779A>G	p.Gln260Arg	missense	Exon 6 of 18	ENSP00000389714.1
	CTNNA3	ENST00000682758.1		c.779A>G	p.Gln260Arg	missense	Exon 7 of 19	ENSP00000508047.1
	CTNNA3	ENST00000684154.1		c.779A>G	p.Gln260Arg	missense	Exon 6 of 18	ENSP00000508371.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00714

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000819 AC: 206 AN: 251418 AF XY: 0.000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461872 Hom.: 1 Cov.: 31 AF XY: 0.000158 AC XY: 115 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00443 AC: 176 AN: 39698

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111994

Other (OTH) AF: 0.000381 AC: 23 AN: 60396

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00715 AC: 37 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000446 Hom.: 0

Bravo AF: 0.000302

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.058
Sift	Benign	0.52	T
Sift4G	Benign	0.32	T
Polyphen		0.96	D
Vest4		0.16
MVP		0.54
MPC		0.074
ClinPred		0.015	T
GERP RS		5.5
Varity_R		0.073
gMVP		0.13
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs190073606; hg19: chr10-68979429;