NM_006030.4:c.284G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_006030.4(CACNA2D2):c.284G>A(p.Arg95His) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,599,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.26

Publications

2 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012971431).

BP6

Variant 3-50476122-C-T is Benign according to our data. Variant chr3-50476122-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416536.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000158 (24/152360) while in subpopulation EAS AF = 0.00309 (16/5182). AF 95% confidence interval is 0.00194. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	UniProt
CACNA2D2	NM_006030.4	MANE Select	c.284G>A	p.Arg95His	missense	Exon 2 of 38	NP_006021.2	Q9NY47-2
CACNA2D2	NM_001174051.3		c.284G>A	p.Arg95His	missense	Exon 2 of 39	NP_001167522.1	Q9NY47-1
CACNA2D2	NM_001005505.3		c.284G>A	p.Arg95His	missense	Exon 2 of 38	NP_001005505.1	Q9NY47-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.284G>A	p.Arg95His	missense	Exon 2 of 38	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6	TSL:5	c.284G>A	p.Arg95His	missense	Exon 2 of 39	ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000479441.1	TSL:1	c.284G>A	p.Arg95His	missense	Exon 2 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000446

AC:

101

AN:

226484

AF XY:

0.000375

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00454

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

260

AN:

1446766

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

117

AN XY:

718446

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33240

American (AMR)

AF:

0.0000460

AC:

AN:

43454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00222

AC:

AN:

39162

South Asian (SAS)

AF:

0.0000358

AC:

AN:

83682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50650

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000136

AC:

150

AN:

1105158

Other (OTH)

AF:

0.000217

AC:

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000158

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00309

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000181

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CACNA2D2-related disorder (1)

Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0099

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

4.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Benign

0.087

Sift4G

Benign

0.11

Polyphen

0.99

Vest4

0.73

MVP

0.17

MPC

0.64

ClinPred

0.042

GERP RS

5.0

Varity_R

0.087

gMVP

0.37

Mutation Taster

=67/33

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

Computational scores

Splicing

Publications

Other links and lift over