chr3-50364667-C-G

Variant names:

• chr3-50364667-C-G
• rs1487559434
• NM_006030.4:c.3431G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_006030.4(CACNA2D2):​c.3431G>C​(p.Ter1144Serext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,370,666 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. Synonymous variant affecting the same amino acid position has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_006030.4 Downstream stopcodon found after 10 codons.

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.3431G>C	p.Ter1144Serext*?	stop_lost	Exon 38 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.3452G>C	p.Ter1151Serext*?	stop_lost	Exon 39 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.3437G>C	p.Ter1146Serext*?	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.3431G>C	p.Ter1144Serext*?	stop_lost	Exon 38 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3461G>C	p.Ter1154Serext*?	stop_lost	Exon 39 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000266039.7	TSL:1	c.3437G>C	p.Ter1146Serext*?	stop_lost	Exon 38 of 38	ENSP00000266039.3	Q9NY47-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1370666 Hom.: 0 Cov.: 32 AF XY: 0.00000297 AC XY: 2 AN XY: 673604

African (AFR) AF: 0.00 AC: 0 AN: 30378

American (AMR) AF: 0.00 AC: 0 AN: 30866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23822

East Asian (EAS) AF: 0.00 AC: 0 AN: 35356

South Asian (SAS) AF: 0.00 AC: 0 AN: 76804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4034

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1065384

Other (OTH) AF: 0.00 AC: 0 AN: 56602

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.86
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.54	D
PhyloP100		0.079
Vest4		0.23
GERP RS		3.8
Mutation Taster		=50/150	disease causing

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: rs1487559434; hg19: chr3-50402098;