rs115276158

chr10-66766350-G-T

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 415371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-66766350-G-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4	c.1195C>A	p.Leu399Ile	missense_variant	9/18	ENST00000433211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7	c.1195C>A	p.Leu399Ile	missense_variant	9/18	1	NM_013266.4	P1

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

GnomAD3 exomes AF: 0.000554 AC: 139 AN: 250886 Hom.: 1 AF XY: 0.000398 AC XY: 54 AN XY: 135562

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 SAS 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

Gnomad4 AFR exome AF: 0.00592

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.000629

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

Gnomad4 AFR AF: 0.00554

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000419 Hom.: 0

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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	- -

Arrhythmogenic right ventricular dysplasia 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
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

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

LitVar

Other links and lift over

dbSNP: rs115276158; hg19: chr10-68526108;