NM_006030.4:c.3421_3430delCGCCGCCTCT

Variant names:

• chr3-50364667-CAGAGGCGGCG-C
• rs2109393712
• NM_006030.4:c.3421_3430delCGCCGCCTCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006030.4(CACNA2D2):​c.3421_3430delCGCCGCCTCT​(p.Arg1141GlufsTer29) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R1141R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA2D2 NM_006030.4 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.3421_3430delCGCCGCCTCT	p.Arg1141GlufsTer29	frameshift stop_lost	Exon 38 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.3442_3451delCGCCGCCTCT	p.Arg1148GlufsTer29	frameshift stop_lost	Exon 39 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.3427_3436delCGCCGCCTCT	p.Arg1143GlufsTer29	frameshift stop_lost	Exon 38 of 38	NP_001005505.1	Q9NY47-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.3421_3430delCGCCGCCTCT	p.Arg1141GlufsTer29	frameshift stop_lost	Exon 38 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3451_3460delCGCCGCCTCT	p.Arg1151GlufsTer29	frameshift stop_lost	Exon 39 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000266039.7	TSL:1	c.3427_3436delCGCCGCCTCT	p.Arg1143GlufsTer29	frameshift stop_lost	Exon 38 of 38	ENSP00000266039.3	Q9NY47-3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0

Splicing

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

Other links and lift over

dbSNP: rs2109393712; hg19: chr3-50402098;