12-1832290-T-G

Position:

• chr12-1832290-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172364.5(CACNA2D4):​c.2551+8449A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

Genes affected

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: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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2551+8449A>C		intron_variant		ENST00000382722.10	NP_758952.4
LRTM2	NM_001039029.3	c.658+765T>G		intron_variant		ENST00000299194.6	NP_001034118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2551+8449A>C		intron_variant		1	NM_172364.5	ENSP00000372169.4
LRTM2	ENST00000299194.6	c.658+765T>G		intron_variant		2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000586184.5	c.2551+8449A>C		intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2476+8449A>C		intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2359+8449A>C		intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2359+8449A>C		intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*797+8449A>C		intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.391+8449A>C		intron_variant		1		ENSP00000440231.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4765847; hg19: chr12-1941456;