10-67180365-G-C

Variant names:

• chr10-67180365-G-C
• NM_013266.4:c.999C>G
• CTNNA3 p.Asn333Lys

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013266.4(CTNNA3):​c.999C>G​(p.Asn333Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N333N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.978
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.999C>G	p.Asn333Lys	missense	Exon 7 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.999C>G	p.Asn333Lys	missense	Exon 7 of 18	NP_001120856.1	Q9UI47-1
	CTNNA3	NM_001291133.2		c.1035C>G	p.Asn345Lys	missense	Exon 8 of 9	NP_001278062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.999C>G	p.Asn333Lys	missense	Exon 7 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.999C>G	p.Asn333Lys	missense	Exon 8 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.999C>G	p.Asn333Lys	missense	Exon 7 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.0
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0082	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.98
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
PromoterAI		-0.045	Neutral
Varity_R		0.48
gMVP		0.42
Mutation Taster		=67/33	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-68940123;