3-50365164-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_006030.4(CACNA2D2):​c.3119T>C​(p.Leu1040Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L1040L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA2D2
NM_006030.4 missense

Scores

9
7
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.40

Publications

10 publications found
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]
CACNA2D2 Gene-Disease associations (from GenCC):
  • cerebellar atrophy with seizures and variable developmental delay
    Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • complex neurodevelopmental disorder
    Inheritance: AR Classification: MODERATE Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 3-50365164-A-G is Pathogenic according to our data. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA2D2NM_006030.4 linkc.3119T>C p.Leu1040Pro missense_variant Exon 36 of 38 ENST00000424201.7 NP_006021.2 Q9NY47-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA2D2ENST00000424201.7 linkc.3119T>C p.Leu1040Pro missense_variant Exon 36 of 38 1 NM_006030.4 ENSP00000390329.2 Q9NY47-2
CACNA2D2ENST00000423994.6 linkc.3143T>C p.Leu1048Pro missense_variant Exon 37 of 39 5 ENSP00000407393.2 C9JVC9
CACNA2D2ENST00000266039.7 linkc.3119T>C p.Leu1040Pro missense_variant Exon 36 of 38 1 ENSP00000266039.3 Q9NY47-3
CACNA2D2ENST00000360963.7 linkc.2912T>C p.Leu971Pro missense_variant Exon 36 of 38 1 ENSP00000354228.3 Q9NY47-4
ENSG00000272104ENST00000606589.1 linkc.128-1133A>G intron_variant Intron 2 of 3 3 ENSP00000476225.1 U3KQU4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Cerebellar atrophy with seizures and variable developmental delay Pathogenic:1
Feb 01, 2013
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.034
.;T;.;.;.;T
Eigen
Pathogenic
0.68
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.3
.;.;.;.;.;M
PhyloP100
8.4
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-4.9
D;D;D;D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
1.0, 1.0
.;.;.;.;D;D
Vest4
0.97
MutPred
0.87
.;.;.;.;.;Loss of stability (P = 0.0089);
MVP
0.73
MPC
1.8
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.85
gMVP
0.83
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs587776948; hg19: chr3-50402595; API