rs536869186

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006030.4(CACNA2D2):c.115G>C(p.Gly39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000475 in 842,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.699

Publications

1 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

CACNA2D2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07447451).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006030.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA2D2	NM_006030.4	MANE Select	c.115G>C	p.Gly39Arg	missense	Exon 1 of 38	NP_006021.2
CACNA2D2	NM_001174051.3		c.115G>C	p.Gly39Arg	missense	Exon 1 of 39	NP_001167522.1
CACNA2D2	NM_001005505.3		c.115G>C	p.Gly39Arg	missense	Exon 1 of 38	NP_001005505.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.115G>C	p.Gly39Arg	missense	Exon 1 of 38	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	TSL:5	c.115G>C	p.Gly39Arg	missense	Exon 1 of 39	ENSP00000407393.2
CACNA2D2	ENST00000479441.1	TSL:1	c.115G>C	p.Gly39Arg	missense	Exon 1 of 39	ENSP00000418081.1

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000433

AC:

AN:

692368

Hom.:

Cov.:

AF XY:

0.00000602

AC XY:

AN XY:

332492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14132

American (AMR)

AF:

0.00

AC:

AN:

6148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9756

East Asian (EAS)

AF:

0.00

AC:

AN:

20146

South Asian (SAS)

AF:

0.00

AC:

AN:

12374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2004

European-Non Finnish (NFE)

AF:

0.00000344

AC:

AN:

580658

Other (OTH)

AF:

0.0000353

AC:

AN:

28366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150534

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41222

American (AMR)

AF:

0.00

AC:

AN:

15124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67544

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Uncertain:1

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 39 of the CACNA2D2 protein (p.Gly39Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1051695). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

9.6

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0054

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

-0.70

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.40

REVEL

Benign

0.022

Sift

Uncertain

0.012

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.17

MutPred

0.27

Gain of glycosylation at P36 (P = 0.0612)

MVP

0.043

MPC

0.20

ClinPred

0.084

GERP RS

-1.2

PromoterAI

-0.046

Neutral

(source)

Varity_R

0.11

gMVP

0.20

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over