2-80302530-C-T

Variant names:

• chr2-80302530-C-T
• rs138747880
• NM_178839.5:c.1290G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_178839.5(LRRTM1):​c.1290G>A​(p.Thr430Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,611,556 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: LRRTM1 NM_178839.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.02
• Publications: 0 publications found

Genes affected

LRRTM1 (HGNC:19408): (leucine rich repeat transmembrane neuronal 1) Predicted to be involved in regulation of postsynaptic density assembly and regulation of presynapse assembly. Predicted to act upstream of or within several processes, including long-term synaptic potentiation; negative regulation of receptor internalization; and positive regulation of synapse assembly. Located in endoplasmic reticulum and growth cone. Is active in GABA-ergic synapse. Is integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-80302530-C-T is Benign according to our data. Variant chr2-80302530-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2651085.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM1	NM_178839.5	c.1290G>A	p.Thr430Thr	synonymous_variant	Exon 2 of 2	ENST00000295057.4	NP_849161.2
CTNNA2	NM_001282597.3	c.1057-90681C>T		intron_variant	Intron 7 of 18	ENST00000402739.9	NP_001269526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRTM1	ENST00000295057.4	c.1290G>A	p.Thr430Thr	synonymous_variant	Exon 2 of 2	1	NM_178839.5	ENSP00000295057.3
CTNNA2	ENST00000402739.9	c.1057-90681C>T		intron_variant	Intron 7 of 18	1	NM_001282597.3	ENSP00000384638.4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 37 AN: 249308 AF XY: 0.000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1459550 Hom.: 0 Cov.: 30 AF XY: 0.000172 AC XY: 125 AN XY: 726212

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51158

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1111964

Other (OTH) AF: 0.000232 AC: 14 AN: 60370

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74260

African (AFR) AF: 0.0000725 AC: 3 AN: 41390

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000212

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRRTM1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.74
DANN	Benign	0.91
PhyloP100		-2.0
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs138747880; hg19: chr2-80529655;