10-66280567-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013266.4(CTNNA3):c.1787G>A(p.Ser596Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,606,400 control chromosomes in the GnomAD database, including 122,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S596T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (18019 hom., cov: 32)
  • Exomes 𝑓: 0.37 (104126 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.986

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.454127E-6).
• BP6: Variant 10-66280567-C-T is Benign according to our data. Variant chr10-66280567-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1169338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-66280567-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4	c.1787G>A	p.Ser596Asn	missense_variant	13/18	ENST00000433211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7	c.1787G>A	p.Ser596Asn	missense_variant	13/18	1	NM_013266.4	P1

Frequencies

GnomAD3 genomes AF: 0.468 AC: 70958 AN: 151630 Hom.: 17989 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.466

GnomAD3 exomes AF: 0.404 AC: 99984 AN: 247298 Hom.: 21107 AF XY: 0.398 AC XY: 53264 AN XY: 133794

Gnomad AFR exome AF: 0.677

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.433

Gnomad SAS exome AF: 0.372

Gnomad FIN exome AF: 0.434

Gnomad NFE exome AF: 0.365

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.372 AC: 541384 AN: 1454652 Hom.: 104126 Cov.: 31 AF XY: 0.371 AC XY: 268575 AN XY: 723780

Gnomad4 AFR exome AF: 0.686

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.432

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.388

GnomAD4 genome AF: 0.468 AC: 71039 AN: 151748 Hom.: 18019 Cov.: 32 AF XY: 0.467 AC XY: 34582 AN XY: 74126

Gnomad4 AFR AF: 0.679

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.391

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.464

Alfa AF: 0.379 Hom.: 27035

Bravo AF: 0.475

TwinsUK AF: 0.346 AC: 1282

ALSPAC AF: 0.338 AC: 1304

ESP6500AA AF: 0.670 AC: 2954

ESP6500EA AF: 0.362 AC: 3114

ExAC AF: 0.411 AC: 49943

Asia WGS AF: 0.443 AC: 1535 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2018

This variant is associated with the following publications: (PMID: 31182772, 17209133) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.4
Dann	Benign	0.11
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000075	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.021
ClinPred		0.0013	T
GERP RS		3.2
Varity_R		0.029
gMVP		0.086

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: rs4548513; hg19: chr10-68040325; COSMIC: COSV65590069;