12-1831269-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039029.3(LRTM2):c.402C>A(p.Asp134Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRTM2
NM_001039029.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.181

Variant links:

Genes affected

LRTM2 (HGNC:32443): (leucine rich repeats and transmembrane domains 2) Predicted to enable Roundabout binding activity and heparin binding activity. Predicted to be involved in axon guidance and negative chemotaxis. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRTM2 links:

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

CACNA2D4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024294645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRTM2	NM_001039029.3 linkuse as main transcript	c.402C>A	p.Asp134Glu	missense_variant	4/5	ENST00000299194.6
CACNA2D4	NM_172364.5 linkuse as main transcript	c.2551+9470G>T		intron_variant		ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRTM2	ENST00000299194.6 linkuse as main transcript	c.402C>A	p.Asp134Glu	missense_variant	4/5	2	NM_001039029.3	P1
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.2551+9470G>T		intron_variant		1	NM_172364.5	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250704

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS 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:

6.84e-7

AC:

AN:

1461434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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 submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.402C>A (p.D134E) alteration is located in exon 4 (coding exon 2) of the LRTM2 gene. This alteration results from a C to A substitution at nucleotide position 402, causing the aspartic acid (D) at amino acid position 134 to be replaced by a glutamic acid (E). 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

0.095

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.67

Cadd

Benign

Dann

Benign

0.84

DEOGEN2

Benign

0.014

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.025

M_CAP

Benign

0.015

MetaRNN

Benign

0.024

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.67

N;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.070

N;N;N

REVEL

Benign

0.040

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.068

MutPred

0.31

Loss of stability (P = 0.1102);Loss of stability (P = 0.1102);Loss of stability (P = 0.1102);

MVP

0.32

MPC

0.29

ClinPred

0.018

GERP RS

-0.78

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

4.0

Varity_R

0.047

gMVP

0.45

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over