rs77165728

chr10-66103234-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.62

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]

(HGNC:):

ACMG classification

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: {Uncertain_significance=2, Likely_benign=2}. Variant chr10-66103234-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4	c.1900G>A	p.Glu634Lys	missense_variant	14/18	ENST00000433211.7
LOC105378340	XR_007062172.1	n.226+4417C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7	c.1900G>A	p.Glu634Lys	missense_variant	14/18	1	NM_013266.4	P1
	ENST00000608793.1	n.485+4417C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152160 Hom.: 0 Cov.: 32

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

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

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

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:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 13 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2022

The 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 submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Mar 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

Other links and lift over

dbSNP: rs77165728; hg19: chr10-67862992;