3-50370310-C-G

Variant names:

• chr3-50370310-C-G
• rs371372561
• NM_006030.4:c.2045+10G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006030.4(CACNA2D2):​c.2045+10G>C variant causes a intron change. The variant allele was found at a frequency of 0.00000492 in 1,423,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.2045+10G>C		intron_variant	Intron 23 of 37	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.2045+10G>C		intron_variant	Intron 23 of 37	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.2066+10G>C		intron_variant	Intron 24 of 38	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.2045+10G>C		intron_variant	Intron 23 of 37	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1838+10G>C		intron_variant	Intron 23 of 37	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 195324 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000492 AC: 7 AN: 1423842 Hom.: 0 Cov.: 31 AF XY: 0.00000426 AC XY: 3 AN XY: 704730

African (AFR) AF: 0.0000308 AC: 1 AN: 32470

American (AMR) AF: 0.00 AC: 0 AN: 39484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.00 AC: 0 AN: 37364

South Asian (SAS) AF: 0.00 AC: 0 AN: 81072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000549 AC: 6 AN: 1093444

Other (OTH) AF: 0.00 AC: 0 AN: 59072

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		4.3

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: rs371372561; hg19: chr3-50407741;