rs371214569

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4BS1_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

6
13
Splicing: ADA: 0.4407
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
CACNA2D2NM_006030.4 linkuse as main transcriptc.1847G>A p.Arg616Lys missense_variant, splice_region_variant 21/38 ENST00000424201.7 NP_006021.2 Q9NY47-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA2D2ENST00000424201.7 linkuse as main transcriptc.1847G>A p.Arg616Lys missense_variant, splice_region_variant 21/381 NM_006030.4 ENSP00000390329.2 Q9NY47-2
CACNA2D2ENST00000423994.6 linkuse as main transcriptc.1847G>A p.Arg616Lys missense_variant, splice_region_variant 21/395 ENSP00000407393.2 C9JVC9
CACNA2D2ENST00000266039.7 linkuse as main transcriptc.1847G>A p.Arg616Lys missense_variant, splice_region_variant 21/381 ENSP00000266039.3 Q9NY47-3
CACNA2D2ENST00000360963.7 linkuse as main transcriptc.1640G>A p.Arg547Lys missense_variant, splice_region_variant 21/381 ENSP00000354228.3 Q9NY47-4

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
show subpopulations
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
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 23, 2021In 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371214569; hg19: chr3-50413135; API