chr12-1831136-A-C

Position:

• chr12-1831136-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000382722.10(CACNA2D4):​c.2551+9603T>G variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA2D4 ENST00000382722.10 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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]

LRTM2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39920378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRTM2	NM_001039029.3	c.269A>C	p.Asn90Thr	missense_variant	4/5	ENST00000299194.6	NP_001034118.1
CACNA2D4	NM_172364.5	c.2551+9603T>G		intron_variant		ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRTM2	ENST00000299194.6	c.269A>C	p.Asn90Thr	missense_variant	4/5	2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000382722.10	c.2551+9603T>G		intron_variant		1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2551+9603T>G		intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2476+9603T>G		intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2359+9603T>G		intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2359+9603T>G		intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*797+9603T>G		intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.391+9603T>G		intron_variant		1		ENSP00000440231.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Sep 13, 2023

The c.269A>C (p.N90T) alteration is located in exon 4 (coding exon 2) of the LRTM2 gene. This alteration results from a A to C substitution at nucleotide position 269, causing the asparagine (N) at amino acid position 90 to be replaced by a threonine (T). 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	0.47
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.34	N
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.8	L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;N;N;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.023	D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;D;D
Polyphen		0.90	P;P;P;.;.
Vest4		0.52
MutPred		0.41		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.78
MPC		0.96
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.41
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1162405704; hg19: chr12-1940302;