chr10-66766350-G-T

Variant names:

• chr10-66766350-G-T
• rs115276158
• NM_013266.4:c.1195C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013266.4(CTNNA3):​c.1195C>A​(p.Leu399Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,613,590 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.91
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017207533).
• BP6: Variant 10-66766350-G-T is Benign according to our data. Variant chr10-66766350-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 257 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.1195C>A	p.Leu399Ile	missense	Exon 9 of 18	NP_037398.2
	CTNNA3	NM_001127384.3		c.1195C>A	p.Leu399Ile	missense	Exon 9 of 18	NP_001120856.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.1195C>A	p.Leu399Ile	missense	Exon 9 of 18	ENSP00000389714.1
	CTNNA3	ENST00000682758.1		c.1195C>A	p.Leu399Ile	missense	Exon 10 of 19	ENSP00000508047.1
	CTNNA3	ENST00000684154.1		c.1195C>A	p.Leu399Ile	missense	Exon 9 of 18	ENSP00000508371.1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152020 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000554 AC: 139 AN: 250886 AF XY: 0.000398

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000244 AC: 357 AN: 1461454 Hom.: 2 Cov.: 31 AF XY: 0.000256 AC XY: 186 AN XY: 727044

African (AFR) AF: 0.00592 AC: 198 AN: 33462

American (AMR) AF: 0.000358 AC: 16 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.0000693 AC: 77 AN: 1111714

Other (OTH) AF: 0.000629 AC: 38 AN: 60378

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152136 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74382

African (AFR) AF: 0.00554 AC: 230 AN: 41510

American (AMR) AF: 0.000327 AC: 5 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67998

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000661 Hom.: 1

Bravo AF: 0.00200

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.74
MVP		0.78
MPC		0.11
ClinPred		0.022	T
GERP RS		6.2
Varity_R		0.27
gMVP		0.16
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

Other links and lift over

dbSNP: rs115276158; hg19: chr10-68526108;