3-50364972-TGG-CGC

Variant names:

• chr3-50364972-TGG-CGC
• ENST00000423994.6:c.3235_3237delCCAinsGCG
• CACNA2D2 p.Pro1079Ala

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_006030.4(CACNA2D2):​c.3209-4_3209-2delCCAinsGCG variant causes a splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D2 NM_006030.4 splice_acceptor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.52
• 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

ENSG00000272104 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006030.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	NM_006030.4	MANE Select	c.3209-4_3209-2delCCAinsGCG		splice_acceptor splice_region intron	N/A	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001005505.3		c.3211_3213delCCAinsGCG	p.Pro1071Ala	missense splice_region	N/A	NP_001005505.1	Q9NY47-3
	CACNA2D2	NM_001291101.1		c.3004_3006delCCAinsGCG	p.Pro1002Ala	missense splice_region	N/A	NP_001278030.1	Q9NY47-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000423994.6	TSL:5	c.3235_3237delCCAinsGCG	p.Pro1079Ala	missense splice_region	N/A	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000266039.7	TSL:1	c.3211_3213delCCAinsGCG	p.Pro1071Ala	missense splice_region	N/A	ENSP00000266039.3	Q9NY47-3
	CACNA2D2	ENST00000360963.7	TSL:1	c.3004_3006delCCAinsGCG	p.Pro1002Ala	missense splice_region	N/A	ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-50402403;