3-50476182-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006030.4(CACNA2D2):c.224G>A(p.Arg75Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0274 in 1,594,440 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 47 hom., cov: 32)

Exomes 𝑓: 0.028 ( 734 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.26

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064392984).

BP6

Variant 3-50476182-C-T is Benign according to our data. Variant chr3-50476182-C-T is described in ClinVar as Benign. ClinVar VariationId is 218531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0189 (2886/152322) while in subpopulation NFE AF = 0.0309 (2105/68020). AF 95% confidence interval is 0.0298. There are 47 homozygotes in GnomAd4. There are 1335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 38	ENST00000424201.7	NP_006021.2	Q9NY47-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D2	ENST00000424201.7 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.17G>A	p.Arg6Gln	missense_variant	Exon 2 of 38	1		ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2888

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00639

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0181

AC:

3933

AN:

217570

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.00491

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.00401

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0283

AC:

40806

AN:

1442118

Hom.:

734

Cov.:

AF XY:

0.0276

AC XY:

19747

AN XY:

715732

show subpopulations

African (AFR)

AF:

0.00413

AC:

137

AN:

33144

American (AMR)

AF:

0.00607

AC:

261

AN:

43010

Ashkenazi Jewish (ASJ)

AF:

0.00368

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

38930

South Asian (SAS)

AF:

0.00455

AC:

379

AN:

83350

European-Finnish (FIN)

AF:

0.0302

AC:

1484

AN:

49178

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0337

AC:

37132

AN:

1103280

Other (OTH)

AF:

0.0217

AC:

1296

AN:

59650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

1931

3861

5792

7722

9653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1370

2740

4110

5480

6850

<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:

0.0189

AC:

2886

AN:

152322

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1335

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00637

AC:

265

AN:

41578

American (AMR)

AF:

0.0101

AC:

154

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0279

AC:

296

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0309

AC:

2105

AN:

68020

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

148

296

443

591

739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0264

Hom.:

214

Bravo

AF:

0.0166

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0358

AC:

138

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0314

AC:

270

ExAC

AF:

0.0171

AC:

2069

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 16, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Feb 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0064

.;T;.;.;.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

MetaRNN

Benign

0.0064

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;L;.;L;L

PhyloP100

4.3

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.31

N;N;N;N;N;N

REVEL

Benign

0.064

Sift

Benign

0.19

T;T;T;D;T;T

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.98, 0.96

.;.;.;.;D;D

Vest4

0.24

MPC

0.20

ClinPred

0.0073

GERP RS

5.0

Varity_R

0.099

gMVP

0.22

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over