2-80302637-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000295057.4(LRRTM1):​c.1183G>A​(p.Ala395Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000361 in 1,607,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

LRRTM1
ENST00000295057.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.667
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.034348667).
BS2
High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRTM1NM_178839.5 linkuse as main transcriptc.1183G>A p.Ala395Thr missense_variant 2/2 ENST00000295057.4 NP_849161.2
CTNNA2NM_001282597.3 linkuse as main transcriptc.1057-90574C>T intron_variant ENST00000402739.9 NP_001269526.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRTM1ENST00000295057.4 linkuse as main transcriptc.1183G>A p.Ala395Thr missense_variant 2/21 NM_178839.5 ENSP00000295057 P1
CTNNA2ENST00000402739.9 linkuse as main transcriptc.1057-90574C>T intron_variant 1 NM_001282597.3 ENSP00000384638 P26232-1

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000458
AC:
11
AN:
240022
Hom.:
0
AF XY:
0.0000381
AC XY:
5
AN XY:
131330
show subpopulations
Gnomad AFR exome
AF:
0.000403
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.0000261
AC:
38
AN:
1455042
Hom.:
0
Cov.:
30
AF XY:
0.0000207
AC XY:
15
AN XY:
723690
show subpopulations
Gnomad4 AFR exome
AF:
0.000748
Gnomad4 AMR exome
AF:
0.0000673
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.000458
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000567
Hom.:
0
Bravo
AF:
0.000132
ESP6500AA
AF:
0.000913
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 20, 2024The c.1183G>A (p.A395T) alteration is located in exon 2 (coding exon 1) of the LRRTM1 gene. This alteration results from a G to A substitution at nucleotide position 1183, causing the alanine (A) at amino acid position 395 to be replaced by a threonine (T). 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
0.064
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
6.0
DANN
Benign
0.86
DEOGEN2
Benign
0.017
T;T
Eigen
Benign
-0.95
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.34
.;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.034
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.79
N;N
REVEL
Benign
0.053
Sift
Benign
0.63
T;T
Sift4G
Benign
0.60
T;T
Polyphen
0.27
B;B
Vest4
0.029
MVP
0.21
ClinPred
0.014
T
GERP RS
3.3
Varity_R
0.041
gMVP
0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147965918; hg19: chr2-80529762; API