Genetic Variant CACNA2D2:p.Gly39Arg (chr3-50503309-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006030.4(CACNA2D2):c.115G>A(p.Gly39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 843,012 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006458521).

BP6

Variant 3-50503309-C-T is Benign according to our data. Variant chr3-50503309-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240274.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00177 (266/150644) while in subpopulation AFR AF = 0.00627 (259/41340). AF 95% confidence interval is 0.00564. There are 3 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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>A	p.Gly39Arg	missense	Exon 1 of 38	NP_006021.2
CACNA2D2	NM_001174051.3		c.115G>A	p.Gly39Arg	missense	Exon 1 of 39	NP_001167522.1
CACNA2D2	NM_001005505.3		c.115G>A	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>A	p.Gly39Arg	missense	Exon 1 of 38	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	TSL:5	c.115G>A	p.Gly39Arg	missense	Exon 1 of 39	ENSP00000407393.2
CACNA2D2	ENST00000479441.1	TSL:1	c.115G>A	p.Gly39Arg	missense	Exon 1 of 39	ENSP00000418081.1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

267

AN:

150534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000463

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:

0.00

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.000176

AC:

122

AN:

692368

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

332492

show subpopulations

African (AFR)

AF:

0.00708

AC:

100

AN:

14132

American (AMR)

AF:

0.00163

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:

0.000353

AC:

AN:

28366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

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:

0.00177

AC:

266

AN:

150644

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

128

AN XY:

73584

show subpopulations

African (AFR)

AF:

0.00627

AC:

259

AN:

41340

American (AMR)

AF:

0.000396

AC:

AN:

15144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67534

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0000696

Hom.:

Bravo

AF:

0.00191

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.115G>A (p.G39R) alteration is located in exon 1 (coding exon 1) of the CACNA2D2 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the glycine (G) at amino acid position 39 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Developmental and epileptic encephalopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0054

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

-0.70

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.40

REVEL

Benign

0.020

Sift

Uncertain

0.012

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.17

MutPred

0.27

Gain of glycosylation at P36 (P = 0.0612)

MVP

0.043

MPC

0.20

ClinPred

0.085

GERP RS

-1.2

PromoterAI

0.0097

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over