chr12-1831409-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_001039029.3(LRTM2):c.542G>A(p.Arg181Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
LRTM2
NM_001039029.3 missense
NM_001039029.3 missense
Scores
2
7
9
Clinical Significance
Conservation
PhyloP100: 9.99
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]
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.76
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRTM2 | NM_001039029.3 | c.542G>A | p.Arg181Gln | missense_variant | 4/5 | ENST00000299194.6 | |
CACNA2D4 | NM_172364.5 | c.2551+9330C>T | intron_variant | ENST00000382722.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRTM2 | ENST00000299194.6 | c.542G>A | p.Arg181Gln | missense_variant | 4/5 | 2 | NM_001039029.3 | P1 | |
CACNA2D4 | ENST00000382722.10 | c.2551+9330C>T | intron_variant | 1 | NM_172364.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461826Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727226
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
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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 | Jun 12, 2023 | The c.542G>A (p.R181Q) alteration is located in exon 4 (coding exon 2) of the LRTM2 gene. This alteration results from a G to A substitution at nucleotide position 542, causing the arginine (R) at amino acid position 181 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
T;T;T
Polyphen
D;D;D
Vest4
MutPred
Loss of phosphorylation at T183 (P = 0.0812);Loss of phosphorylation at T183 (P = 0.0812);Loss of phosphorylation at T183 (P = 0.0812);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at