rs2887631

Positions:

• chr12-1825415-G-A
• chr12-1825415-G-C
• chr12-1825415-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172364.5(CACNA2D4):​c.2552-13692C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.735 in 152,122 control chromosomes in the GnomAD database, including 41,266 homozygotes. 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: 𝑓 0.74 (41266 hom., cov: 33)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2552-13692C>T		intron_variant		ENST00000382722.10	NP_758952.4
LRTM2	NM_001039029.3	c.-258-1995G>A		intron_variant		ENST00000299194.6	NP_001034118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2552-13692C>T		intron_variant		1	NM_172364.5	ENSP00000372169.4
LRTM2	ENST00000299194.6	c.-258-1995G>A		intron_variant		2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000586184.5	c.2552-13692C>T		intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2477-13692C>T		intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2360-13692C>T		intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2360-13692C>T		intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*798-14828C>T		intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.392-13692C>T		intron_variant		1		ENSP00000440231.2

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111758 AN: 152004 Hom.: 41246 Cov.: 33

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.733

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

GnomAD4 genome AF: 0.735 AC: 111819 AN: 152122 Hom.: 41266 Cov.: 33 AF XY: 0.739 AC XY: 54951 AN XY: 74380

Gnomad4 AFR AF: 0.721

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.753

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.614

Gnomad4 FIN AF: 0.822

Gnomad4 NFE AF: 0.724

Gnomad4 OTH AF: 0.732

Alfa AF: 0.718 Hom.: 21426

Bravo AF: 0.733

Asia WGS AF: 0.728 AC: 2532 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.89
DANN	Benign	0.75

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: rs2887631; hg19: chr12-1934581;