chr3-50367891-G-A

Position:

• chr3-50367891-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006030.4(CACNA2D2):​c.2155C>T​(p.Leu719Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000762 in 1,312,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L719I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA2D2. . Gene score misZ 2.9999 (greater than the threshold 3.09). Trascript score misZ 3.123 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar atrophy with seizures and variable developmental delay, complex neurodevelopmental disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4	c.2155C>T	p.Leu719Phe	missense_variant	25/38	ENST00000424201.7
LOC101928965	NR_183064.1	n.1065G>A		non_coding_transcript_exon_variant	2/2
LOC127898564	NR_183066.1	n.965G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.2155C>T	p.Leu719Phe	missense_variant	25/38	1	NM_006030.4	P4
	ENST00000607121.5	n.698G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.62e-7 AC: 1 AN: 1312620 Hom.: 0 Cov.: 36 AF XY: 0.00000152 AC XY: 1 AN XY: 655906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 719 of the CACNA2D2 protein (p.Leu719Phe). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 411010). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;.;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D
MetaSVM	Uncertain	0.049	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;D;D
Vest4		0.81
MutPred		0.56		Loss of helix (P = 0.0376);.;.;.;.;Loss of helix (P = 0.0376);
MVP		0.55
MPC		1.4
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.67
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs998005566; hg19: chr3-50405322;