rs746371451

chr3-50367445-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP3_Moderate BS1_Supporting

The NM_006030.4(CACNA2D2):c.2350C>T(p.Arg784Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R784H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.13

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA2D2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000591 (9/152184) while in subpopulation NFE AF= 0.0000882 (6/68028). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4	c.2350C>T	p.Arg784Cys	missense_variant	27/38	ENST00000424201.7
LOC101928965	NR_183064.1	n.970-351G>A		intron_variant, non_coding_transcript_variant
LOC127898564	NR_183066.1	n.870-351G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.2350C>T	p.Arg784Cys	missense_variant	27/38	1	NM_006030.4	P4
	ENST00000607121.5	n.603-351G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000759 AC: 19 AN: 250334 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135710

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1461652 Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 81 AN XY: 727104

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74342

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000742 AC: 9

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2021

The c.2371C>T (p.R791C) alteration is located in exon 28 (coding exon 28) of the CACNA2D2 gene. This alteration results from a C to T substitution at nucleotide position 2371, causing the arginine (R) at amino acid position 791 to be replaced by a cysteine (C). The in silico prediction for the p.R791C alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 784 of the CACNA2D2 protein (p.Arg784Cys). This variant is present in population databases (rs746371451, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 461312). 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. 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;D;D
Vest4		0.88
MVP		0.72
MPC		1.6
ClinPred		0.64	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs746371451; hg19: chr3-50404876;