rs368699159

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_006030.4(CACNA2D2):ā€‹c.2297A>Cā€‹(p.Lys766Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000685 in 1,459,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000069 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense, splice_region

Scores

2
6
11
Splicing: ADA: 0.1970
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62
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]

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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=0.25622568).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA2D2NM_006030.4 linkuse as main transcriptc.2297A>C p.Lys766Thr missense_variant, splice_region_variant 26/38 ENST00000424201.7
LOC101928965NR_183064.1 linkuse as main transcriptn.970-154T>G intron_variant, non_coding_transcript_variant
LOC127898564NR_183066.1 linkuse as main transcriptn.870-154T>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA2D2ENST00000424201.7 linkuse as main transcriptc.2297A>C p.Lys766Thr missense_variant, splice_region_variant 26/381 NM_006030.4 P4Q9NY47-2
ENST00000607121.5 linkuse as main transcriptn.603-154T>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000685
AC:
10
AN:
1459422
Hom.:
0
Cov.:
34
AF XY:
0.00000827
AC XY:
6
AN XY:
725540
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000901
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000624
Hom.:
0
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
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), LabcorpAug 12, 2021Algorithms 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA2D2-related disease. This variant is present in population databases (rs368699159, ExAC 0.002%). This sequence change replaces lysine with threonine at codon 766 of the CACNA2D2 protein (p.Lys766Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. 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
Benign
0.22
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0026
.;T;.;.;.;T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.26
T;T;T;T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
1.9
.;.;.;.;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.27
N;N;N;N;N;N
REVEL
Uncertain
0.30
Sift
Benign
0.32
T;T;T;T;T;T
Sift4G
Benign
0.32
T;T;T;T;T;T
Polyphen
0.61, 0.15
.;.;.;.;P;B
Vest4
0.52
MVP
0.53
MPC
0.87
ClinPred
0.33
T
GERP RS
5.4
Varity_R
0.13
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.20
dbscSNV1_RF
Benign
0.54
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

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

Other links and lift over

dbSNP: rs368699159; hg19: chr3-50405073; API