3-50402995-A-G

Variant names:

• chr3-50402995-A-G
• rs2236957
• NM_006030.4:c.406-8827T>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.406-8827T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 151,938 control chromosomes in the GnomAD database, including 8,905 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 (8905 hom., cov: 32)
• Consequence: CACNA2D2 NM_006030.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.966
• Publications: 7 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.406-8827T>C		intron_variant	Intron 3 of 37	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.406-8827T>C		intron_variant	Intron 3 of 37	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.406-8827T>C		intron_variant	Intron 3 of 38	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.406-8827T>C		intron_variant	Intron 3 of 37	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.199-8827T>C		intron_variant	Intron 3 of 37	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43797 AN: 151818 Hom.: 8864 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.289 AC: 43888 AN: 151938 Hom.: 8905 Cov.: 32 AF XY: 0.288 AC XY: 21429 AN XY: 74296

African (AFR) AF: 0.538 AC: 22273 AN: 41392

American (AMR) AF: 0.390 AC: 5951 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2441 AN: 5146

South Asian (SAS) AF: 0.129 AC: 624 AN: 4822

European-Finnish (FIN) AF: 0.156 AC: 1648 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9956 AN: 67966

Other (OTH) AF: 0.241 AC: 508 AN: 2112

Alfa AF: 0.245 Hom.: 877

Bravo AF: 0.322

Asia WGS AF: 0.291 AC: 1012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.71
PhyloP100		-0.97
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: rs2236957; hg19: chr3-50440426;