rs3815325

Positions:

• chr12-1795925-G-A

Variant summary

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

The NM_172364.5(CACNA2D4):​c.3114-145C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 652,156 control chromosomes in the GnomAD database, including 20,219 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 0.27 (6345 hom., cov: 32)
  • Exomes 𝑓: 0.23 (13874 hom.)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.781

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.3114-145C>T		intron_variant		ENST00000382722.10	NP_758952.4
CACNA2D4	XM_011521041.3	c.3051-145C>T		intron_variant			XP_011519343.1
CACNA2D4	XM_047429897.1	c.3042-145C>T		intron_variant			XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.3114-145C>T		intron_variant		1	NM_172364.5	ENSP00000372169	P2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41717 AN: 152020 Hom.: 6334 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.230 AC: 114783 AN: 500018 Hom.: 13874 Cov.: 4 AF XY: 0.232 AC XY: 62119 AN XY: 268224

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.245

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.243

GnomAD4 genome AF: 0.275 AC: 41767 AN: 152138 Hom.: 6345 Cov.: 32 AF XY: 0.271 AC XY: 20183 AN XY: 74386

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.247

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.277

Alfa AF: 0.252 Hom.: 1184

Bravo AF: 0.289

Asia WGS AF: 0.286 AC: 994 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.37

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: rs3815325; hg19: chr12-1905091; COSMIC: COSV54957961; COSMIC: COSV54957961;