rs371214569

Positions:

• chr3-50375704-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BS1_Supporting

The NM_006030.4(CACNA2D2):​c.1847G>A​(p.Arg616Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000363 in 1,461,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense, splice_region
• Scores: Splicing: ADA: 0.4407
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.372585).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000363 (53/1461084) while in subpopulation NFE AF= 0.0000459 (51/1111952). AF 95% confidence interval is 0.0000355. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 35. 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	Protein	UniProt
CACNA2D2	NM_006030.4	c.1847G>A	p.Arg616Lys	missense_variant, splice_region_variant	21/38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.1847G>A	p.Arg616Lys	missense_variant, splice_region_variant	21/38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.1847G>A	p.Arg616Lys	missense_variant, splice_region_variant	21/39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.1847G>A	p.Arg616Lys	missense_variant, splice_region_variant	21/38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1640G>A	p.Arg547Lys	missense_variant, splice_region_variant	21/38	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461084 Hom.: 0 Cov.: 35 AF XY: 0.0000385 AC XY: 28 AN XY: 726850

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2021

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 530497). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 616 of the CACNA2D2 protein (p.Arg616Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0073	.;T;.;.;.;T
Eigen	Benign	0.055
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	.;.;L;.;L;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.88	N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.45	T;T;T;T;T;T
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		0.72, 0.37	.;.;.;.;P;B
Vest4		0.49
MVP		0.51
MPC		0.85
ClinPred		0.74	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.80		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs371214569; hg19: chr3-50413135;