2-79858055-C-T

Position:

• chr2-79858055-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001282597.3(CTNNA2):​c.341C>T​(p.Pro114Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA2 NM_001282597.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNA2. . Gene score misZ 3.6298 (greater than the threshold 3.09). Trascript score misZ 3.6837 (greater than threshold 3.09). GenCC has associacion of gene with cortical dysplasia, complex, with other brain malformations 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNA2	NM_001282597.3	c.341C>T	p.Pro114Leu	missense_variant	4/19	ENST00000402739.9	NP_001269526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNA2	ENST00000402739.9	c.341C>T	p.Pro114Leu	missense_variant	4/19	1	NM_001282597.3	ENSP00000384638.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.341C>T (p.P114L) alteration is located in exon 4 (coding exon 3) of the CTNNA2 gene. This alteration results from a C to T substitution at nucleotide position 341, causing the proline (P) at amino acid position 114 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	.;.;.;T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Uncertain	2.6	M;M;M;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.4	D;D;.;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.94
MutPred		0.79		Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);
MVP		0.81
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-80085181;