rs12494849

Variant names:

• chr3-50487127-C-G
• rs12494849
• NM_006030.4:c.207-10928G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006030.4(CACNA2D2):​c.207-10928G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,158 control chromosomes in the GnomAD database, including 9,286 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 0.29 (9286 hom., cov: 33)
• Consequence: CACNA2D2 NM_006030.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 5 publications found

Genes affected

CACNA2D2 (HGNC:1400): (calcium voltage-gated channel auxiliary subunit alpha2delta 2) Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

CACNA2D2 Gene-Disease associations (from GenCC):

• cerebellar atrophy with seizures and variable developmental delay

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.207-10928G>C		intron_variant	Intron 1 of 37	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.207-10928G>C		intron_variant	Intron 1 of 37	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.207-10928G>C		intron_variant	Intron 1 of 38	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.207-10928G>C		intron_variant	Intron 1 of 37	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.-1-10928G>C		intron_variant	Intron 1 of 37	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44518 AN: 152040 Hom.: 9251 Cov.: 33

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.256

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

GnomAD4 genome AF: 0.293 AC: 44613 AN: 152158 Hom.: 9286 Cov.: 33 AF XY: 0.293 AC XY: 21828 AN XY: 74404

African (AFR) AF: 0.537 AC: 22263 AN: 41466

American (AMR) AF: 0.382 AC: 5848 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3470

East Asian (EAS) AF: 0.619 AC: 3195 AN: 5164

South Asian (SAS) AF: 0.129 AC: 620 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1566 AN: 10614

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10023 AN: 68006

Other (OTH) AF: 0.258 AC: 543 AN: 2108

Alfa AF: 0.236 Hom.: 773

Bravo AF: 0.326

Asia WGS AF: 0.333 AC: 1160 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.9
DANN	Benign	0.67
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12494849; hg19: chr3-50524558;