NM_178839.5:c.1104G>C

Variant names:

• chr2-80302716-C-G
• rs1416271114
• NM_178839.5:c.1104G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_178839.5(LRRTM1):​c.1104G>C​(p.Glu368Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LRRTM1 NM_178839.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056468964).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM1	NM_178839.5	c.1104G>C	p.Glu368Asp	missense_variant	Exon 2 of 2	ENST00000295057.4	NP_849161.2
CTNNA2	NM_001282597.3	c.1057-90495C>G		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.1104G>C	p.Glu368Asp	missense_variant	Exon 2 of 2	1	NM_178839.5	ENSP00000295057.3
CTNNA2	ENST00000402739.9	c.1057-90495C>G		intron_variant	Intron 7 of 18	1	NM_001282597.3	ENSP00000384638.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460528 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726568

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111778

Other (OTH) AF: 0.0000497 AC: 3 AN: 60346

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1104G>C (p.E368D) alteration is located in exon 2 (coding exon 1) of the LRRTM1 gene. This alteration results from a G to C substitution at nucleotide position 1104, causing the glutamic acid (E) at amino acid position 368 to be replaced by an aspartic acid (D). 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	Benign	0.062
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.51	N;N
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.064
Sift	Benign	0.62	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0	B;B
Vest4		0.062
MutPred		0.28		Loss of glycosylation at T370 (P = 0.1175);Loss of glycosylation at T370 (P = 0.1175);
MVP		0.13
ClinPred		0.19	T
GERP RS		3.5
Varity_R		0.094
gMVP		0.29
Mutation Taster		=86/14	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: rs1416271114; hg19: chr2-80529841; COSMIC: COSV54442649; COSMIC: COSV54442649;