2-79651599-A-G

Variant names:

• chr2-79651599-A-G
• rs1681256830
• NM_001282597.3:c.43A>G

Variant summary

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

The NM_001282597.3(CTNNA2):​c.43A>G​(p.Lys15Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CTNNA2 NM_001282597.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.91
• Publications: 0 publications found

Genes affected

CTNNA2 (HGNC:2510): (catenin alpha 2) Enables actin filament binding activity. Involved in negative regulation of Arp2/3 complex-mediated actin nucleation; regulation of neuron migration; and regulation of neuron projection development. Located in cytoplasm. Implicated in complex cortical dysplasia with other brain malformations. [provided by Alliance of Genome Resources, Apr 2022]

CTNNA2 Gene-Disease associations (from GenCC):

• cortical dysplasia, complex, with other brain malformations 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA2	NM_001282597.3	c.43A>G	p.Lys15Glu	missense_variant	Exon 2 of 19	ENST00000402739.9	NP_001269526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA2	ENST00000402739.9	c.43A>G	p.Lys15Glu	missense_variant	Exon 2 of 19	1	NM_001282597.3	ENSP00000384638.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461550 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43A>G (p.K15E) alteration is located in exon 2 (coding exon 1) of the CTNNA2 gene. This alteration results from a A to G substitution at nucleotide position 43, causing the lysine (K) at amino acid position 15 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Mar 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	.;.;T;.;T;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.9	L;L;.;L;.;.;L
PhyloP100		8.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N;N;D;.;D;D;N
REVEL	Benign	0.18
Sift	Benign	0.23	T;T;T;.;T;D;T
Sift4G	Benign	0.097	T;T;D;T;D;D;T
Polyphen		0.0020	B;B;.;B;.;.;P
Vest4		0.77
MutPred		0.31		Loss of ubiquitination at K15 (P = 0.0174);Loss of ubiquitination at K15 (P = 0.0174);Loss of ubiquitination at K15 (P = 0.0174);Loss of ubiquitination at K15 (P = 0.0174);Loss of ubiquitination at K15 (P = 0.0174);Loss of ubiquitination at K15 (P = 0.0174);Loss of ubiquitination at K15 (P = 0.0174);
MVP		0.87
MPC		0.92
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.39
gMVP		0.74
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1681256830; hg19: chr2-79878725;