12-1831066-C-G

Variant names:

• chr12-1831066-C-G
• rs758112424
• NM_001039029.3:c.199C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001039029.3(LRTM2):​c.199C>G​(p.Pro67Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRTM2 NM_001039029.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRTM2	NM_001039029.3	c.199C>G	p.Pro67Ala	missense_variant	Exon 4 of 5	ENST00000299194.6	NP_001034118.1
CACNA2D4	NM_172364.5	c.2551+9673G>C		intron_variant	Intron 26 of 37	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRTM2	ENST00000299194.6	c.199C>G	p.Pro67Ala	missense_variant	Exon 4 of 5	2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000382722.10	c.2551+9673G>C		intron_variant	Intron 26 of 37	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2551+9673G>C		intron_variant	Intron 26 of 36	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2476+9673G>C		intron_variant	Intron 25 of 36	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2359+9673G>C		intron_variant	Intron 26 of 36	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2359+9673G>C		intron_variant	Intron 26 of 37	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*797+9673G>C		intron_variant	Intron 26 of 36	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.391+9673G>C		intron_variant	Intron 4 of 14	1		ENSP00000440231.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251230 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>G (p.P67A) alteration is located in exon 4 (coding exon 2) of the LRTM2 gene. This alteration results from a C to G substitution at nucleotide position 199, causing the proline (P) at amino acid position 67 to be replaced by an alanine (A). 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D;D;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.30	N
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;M;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.2	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.083	T;T;T;D;D
Sift4G	Benign	0.24	T;T;T;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.27
MutPred		0.76		Loss of disorder (P = 0.0727);Loss of disorder (P = 0.0727);Loss of disorder (P = 0.0727);Loss of disorder (P = 0.0727);Loss of disorder (P = 0.0727);
MVP		0.90
MPC		0.57
ClinPred		0.81	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.64

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: rs758112424; hg19: chr12-1940232;