chr2-79869894-G-T

Variant names:

• chr2-79869894-G-T
• NM_001282597.3:c.544G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001282597.3(CTNNA2):​c.544G>T​(p.Glu182*) variant causes a stop gained 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTNNA2 NM_001282597.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.62

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-79869894-G-T is Pathogenic according to our data. Variant chr2-79869894-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3390860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA2	NM_001282597.3	c.544G>T	p.Glu182*	stop_gained	Exon 5 of 19	ENST00000402739.9	NP_001269526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA2	ENST00000402739.9	c.544G>T	p.Glu182*	stop_gained	Exon 5 of 19	1	NM_001282597.3	ENSP00000384638.4
CTNNA2	ENST00000496558.5	c.544G>T	p.Glu182*	stop_gained	Exon 5 of 18	1		ENSP00000419295.1
CTNNA2	ENST00000466387.5	c.544G>T	p.Glu182*	stop_gained	Exon 9 of 22	2		ENSP00000418191.1
CTNNA2	ENST00000629316.2	c.544G>T	p.Glu182*	stop_gained	Exon 5 of 17	2		ENSP00000486160.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cortical dysplasia, complex, with other brain malformations 9 Pathogenic:1

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant is absent in homozygous and/or heterozygous state from the population database gnomAD (v.4.1.0). This variant is predicted to cause introduction of a premature termination codon which may either trigger nonsense-mediated mRNA decay or result in a truncated protein product. There are other truncating variants reported downstream of the above-mentioned variant known to cortical dysplasia, complex, with other brain malformations 9. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.75
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 41

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: chr2-80097020;