12-1831216-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_001039029.3(LRTM2):c.349A>G(p.Asn117Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000164 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LRTM2 NM_001039029.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity LRTM2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.3248064).
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRTM2	NM_001039029.3	c.349A>G	p.Asn117Asp	missense_variant	4/5	ENST00000299194.6
CACNA2D4	NM_172364.5	c.2551+9523T>C		intron_variant		ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRTM2	ENST00000299194.6	c.349A>G	p.Asn117Asp	missense_variant	4/5	2	NM_001039029.3	P1
CACNA2D4	ENST00000382722.10	c.2551+9523T>C		intron_variant		1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 250866 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.000255

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 112 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.000204

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74454

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

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

Aug 01, 2022

The c.349A>G (p.N117D) alteration is located in exon 4 (coding exon 2) of the LRTM2 gene. This alteration results from a A to G substitution at nucleotide position 349, causing the asparagine (N) at amino acid position 117 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	0.29
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.050	T;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.24
MVP		0.64
MPC		0.97
ClinPred		0.31	T
GERP RS		5.0
Varity_R		0.34
gMVP		0.71

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

Other links and lift over

dbSNP: rs143277357; hg19: chr12-1940382;