3-50476159-C-T

Variant names:

• chr3-50476159-C-T
• rs775944051
• NM_006030.4:c.247G>A

Variant summary

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

The NM_006030.4(CACNA2D2):​c.247G>A​(p.Gly83Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,449,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G83G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (1 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26
• Publications: 2 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 (MetaRNN=0.36914334).

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.247G>A	p.Gly83Ser	missense	Exon 2 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.247G>A	p.Gly83Ser	missense	Exon 2 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.247G>A	p.Gly83Ser	missense	Exon 2 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.247G>A	p.Gly83Ser	missense	Exon 2 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.247G>A	p.Gly83Ser	missense	Exon 2 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000479441.1	TSL:1	c.247G>A	p.Gly83Ser	missense	Exon 2 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 228914 AF XY: 0.0000161

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: 0.00000970

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1449706 Hom.: 1 Cov.: 30 AF XY: 0.0000153 AC XY: 11 AN XY: 720124

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 43840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.0000476 AC: 4 AN: 84120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1106958

Other (OTH) AF: 0.0000167 AC: 1 AN: 59972

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.97	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.16	B
Vest4		0.75
MutPred		0.32		Gain of MoRF binding (P = 0.1031)
MVP		0.22
MPC		0.33
ClinPred		0.59	D
GERP RS		5.0
Varity_R		0.070
gMVP		0.33
Mutation Taster		=78/22	polymorphism

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: rs775944051; hg19: chr3-50513590; COSMIC: COSV99818592;