10-65988785-T-G

Variant names:

• chr10-65988785-T-G
• rs116662854
• NM_013266.4:c.2172A>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_013266.4(CTNNA3):​c.2172A>C​(p.Pro724Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,613,278 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P724P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: CTNNA3 NM_013266.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.72
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-65988785-T-G is Benign according to our data. Variant chr10-65988785-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BS2: High AC in GnomAd4 at 304 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.2172A>C	p.Pro724Pro	synonymous	Exon 16 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.2172A>C	p.Pro724Pro	synonymous	Exon 16 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.2172A>C	p.Pro724Pro	synonymous	Exon 16 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.2172A>C	p.Pro724Pro	synonymous	Exon 17 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.2172A>C	p.Pro724Pro	synonymous	Exon 16 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000534 AC: 134 AN: 250840 AF XY: 0.000398

Gnomad AFR exome AF: 0.00715

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1460998 Hom.: 4 Cov.: 30 AF XY: 0.000165 AC XY: 120 AN XY: 726824

African (AFR) AF: 0.00720 AC: 241 AN: 33466

American (AMR) AF: 0.000336 AC: 15 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111450

Other (OTH) AF: 0.000530 AC: 32 AN: 60366

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74476

African (AFR) AF: 0.00683 AC: 284 AN: 41576

American (AMR) AF: 0.000916 AC: 14 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Arrhythmogenic right ventricular dysplasia 13 (1)
-	-	1	CTNNA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.79
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116662854; hg19: chr10-67748543;