chr12-1831286-C-G

Position:

• chr12-1831286-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001039029.3(LRTM2):​c.419C>G​(p.Pro140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,378 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LRTM2 NM_001039029.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

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]

CACNA2D4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12776849).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRTM2	NM_001039029.3	c.419C>G	p.Pro140Arg	missense_variant	4/5	ENST00000299194.6	NP_001034118.1
CACNA2D4	NM_172364.5	c.2551+9453G>C		intron_variant		ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRTM2	ENST00000299194.6	c.419C>G	p.Pro140Arg	missense_variant	4/5	2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000382722.10	c.2551+9453G>C		intron_variant		1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2551+9453G>C		intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2476+9453G>C		intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2359+9453G>C		intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2359+9453G>C		intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*797+9453G>C		intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.391+9453G>C		intron_variant		1		ENSP00000440231.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250676 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

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 AF: 0.00000411 AC: 6 AN: 1461378 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 16, 2024

The c.419C>G (p.P140R) 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 419, causing the proline (P) at amino acid position 140 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.029	T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.019	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.13	B;B;B
Vest4		0.36
MutPred		0.35		Gain of MoRF binding (P = 0.0051);Gain of MoRF binding (P = 0.0051);Gain of MoRF binding (P = 0.0051);
MVP		0.43
MPC		0.43
ClinPred		0.15	T
GERP RS		4.3
Varity_R		0.055
gMVP		0.60

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: rs748621254; hg19: chr12-1940452;