2-80302759-A-G

Variant names:

• chr2-80302759-A-G
• rs775910242
• NM_178839.5:c.1061T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178839.5(LRRTM1):​c.1061T>C​(p.Leu354Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L354Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRTM1 NM_178839.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.31
• Publications: 1 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178839.5. 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
	LRRTM1	NM_178839.5	MANE Select	c.1061T>C	p.Leu354Pro	missense	Exon 2 of 2	NP_849161.2	Q86UE6
	CTNNA2	NM_001282597.3	MANE Select	c.1057-90452A>G		intron	N/A	NP_001269526.1	P26232-1
	CTNNA2	NM_001282598.2		c.1159-90452A>G		intron	N/A	NP_001269527.1	P26232-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRTM1	ENST00000295057.4	TSL:1 MANE Select	c.1061T>C	p.Leu354Pro	missense	Exon 2 of 2	ENSP00000295057.3	Q86UE6
	CTNNA2	ENST00000402739.9	TSL:1 MANE Select	c.1057-90452A>G		intron	N/A	ENSP00000384638.4	P26232-1
	CTNNA2	ENST00000496558.5	TSL:1	c.1057-90452A>G		intron	N/A	ENSP00000419295.1	P26232-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247132 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460884 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726734

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52740

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

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	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.67		Loss of stability (P = 0.008)
MVP		0.62
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.92
Mutation Taster		=1/99	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: rs775910242; hg19: chr2-80529884;