chr3-50367086-C-T

Variant names:

• chr3-50367086-C-T
• rs1553726058
• NM_006030.4:c.2425G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006030.4(CACNA2D2):​c.2425G>A​(p.Glu809Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.2425G>A	p.Glu809Lys	missense_variant	Exon 28 of 38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.2425G>A	p.Glu809Lys	missense_variant	Exon 28 of 38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.2446G>A	p.Glu816Lys	missense_variant	Exon 29 of 39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.2425G>A	p.Glu809Lys	missense_variant	Exon 28 of 38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.2218G>A	p.Glu740Lys	missense_variant	Exon 28 of 38	1		ENSP00000354228.3
ENSG00000272104	ENST00000606589.1	c.*10-710C>T		intron_variant	Intron 3 of 3	3		ENSP00000476225.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Mar 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 809 of the CACNA2D2 protein (p.Glu809Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA2D2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	.;T;.;.;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.8	.;.;.;.;.;L
PhyloP100		7.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.023	D;D;D;T;T;D
Sift4G	Benign	0.078	T;T;T;T;T;T
Polyphen		0.70, 0.65	.;.;.;.;P;P
Vest4		0.73
MutPred		0.49		Gain of sheet (P = 0.0028);.;.;.;.;Gain of sheet (P = 0.0028);
MVP		0.87
MPC		1.3
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.24
gMVP		0.75
Mutation Taster		=58/42	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: rs1553726058; hg19: chr3-50404517;