chr3-50476122-C-G

Position:

• chr3-50476122-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006030.4(CACNA2D2):​c.284G>C​(p.Arg95Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.26

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 (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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.284G>C	p.Arg95Pro	missense_variant	2/38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.284G>C	p.Arg95Pro	missense_variant	2/38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.284G>C	p.Arg95Pro	missense_variant	2/39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.284G>C	p.Arg95Pro	missense_variant	2/38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.77G>C	p.Arg26Pro	missense_variant	2/38	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446768 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	.;T;.;.;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;L;.;L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.091	T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.87, 0.80	.;.;.;.;P;P
Vest4		0.90
MutPred		0.58		Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);.;Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);
MVP		0.25
MPC		0.67
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.85

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: rs149979955; hg19: chr3-50513553;