rs77165728

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_013266.4(CTNNA3):​c.1900G>A​(p.Glu634Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000651 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

CTNNA3
NM_013266.4 missense

Scores

2
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.62
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21713498).
BP6
Variant 10-66103234-C-T is Benign according to our data. Variant chr10-66103234-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240866.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr10-66103234-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CTNNA3NM_013266.4 linkuse as main transcriptc.1900G>A p.Glu634Lys missense_variant 14/18 ENST00000433211.7 NP_037398.2
LOC105378340XR_007062172.1 linkuse as main transcriptn.226+4417C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CTNNA3ENST00000433211.7 linkuse as main transcriptc.1900G>A p.Glu634Lys missense_variant 14/181 NM_013266.4 ENSP00000389714 P1Q9UI47-1
ENST00000608793.1 linkuse as main transcriptn.485+4417C>T intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.000552
AC:
84
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000851
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000941
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000537
AC:
135
AN:
251302
Hom.:
0
AF XY:
0.000596
AC XY:
81
AN XY:
135814
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000231
Gnomad NFE exome
AF:
0.000977
Gnomad OTH exome
AF:
0.000816
GnomAD4 exome
AF:
0.000661
AC:
966
AN:
1461616
Hom.:
0
Cov.:
30
AF XY:
0.000646
AC XY:
470
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000816
Gnomad4 OTH exome
AF:
0.000613
GnomAD4 genome
AF:
0.000552
AC:
84
AN:
152278
Hom.:
0
Cov.:
32
AF XY:
0.000537
AC XY:
40
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000850
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000941
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000715
Hom.:
0
Bravo
AF:
0.000491
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000453
AC:
55
EpiCase
AF:
0.000818
EpiControl
AF:
0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 13 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingPhosphorus, Inc.Aug 01, 2017- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 11, 2022The p.E634K variant (also known as c.1900G>A), located in coding exon 13 of the CTNNA3 gene, results from a G to A substitution at nucleotide position 1900. The glutamic acid at codon 634 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsMar 06, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.22
T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.3
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.19
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.012
D
Polyphen
0.98
D
Vest4
0.58
MVP
0.72
MPC
0.022
ClinPred
0.078
T
GERP RS
5.5
Varity_R
0.30
gMVP
0.41

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77165728; hg19: chr10-67862992; API