12-1828192-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001039029.3(LRTM2):c.44C>T(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,546,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: LRTM2 NM_001039029.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.30

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03704375).
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRTM2	NM_001039029.3	c.44C>T	p.Ala15Val	missense_variant	3/5	ENST00000299194.6
CACNA2D4	NM_172364.5	c.2551+12547G>A		intron_variant		ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRTM2	ENST00000299194.6	c.44C>T	p.Ala15Val	missense_variant	3/5	2	NM_001039029.3	P1
CACNA2D4	ENST00000382722.10	c.2551+12547G>A		intron_variant		1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 34

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000961 AC: 14 AN: 145620 Hom.: 0 AF XY: 0.000129 AC XY: 10 AN XY: 77594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000467

Gnomad SAS exome AF: 0.000313

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000652 AC: 91 AN: 1394802 Hom.: 0 Cov.: 31 AF XY: 0.0000683 AC XY: 47 AN XY: 687872

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.0000848

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000169

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000566

Gnomad4 OTH exome AF: 0.0000692

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000140 AC: 1

ExAC AF: 0.0000708 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.44C>T (p.A15V) alteration is located in exon 3 (coding exon 1) of the LRTM2 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the alanine (A) at amino acid position 15 to be replaced by a valine (V). 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	0.085
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	4.7
Dann	Benign	0.97
DEOGEN2	Benign	0.015	T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.037	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.47	N;N;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.14
MVP		0.60
MPC		0.30
ClinPred		0.010	T
GERP RS		-0.14
Varity_R		0.025
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs368354192; hg19: chr12-1937358;