chr3-50365100-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS1

The NM_006030.4(CACNA2D2):c.3183C>T(p.Gly1061Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,611,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

CACNA2D2
NM_006030.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.07

Publications

0 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:

ENSG00000272104 (HGNC:):

ENSG00000272104 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 3-50365100-G-A is Benign according to our data. Variant chr3-50365100-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 530569.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.08 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000237 (36/152128) while in subpopulation AMR AF = 0.000327 (5/15280). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.3183C>T	p.Gly1061Gly	synonymous_variant	Exon 36 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.3183C>T	p.Gly1061Gly	synonymous_variant	Exon 36 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.3207C>T	p.Gly1069Gly	synonymous_variant	Exon 37 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.3183C>T	p.Gly1061Gly	synonymous_variant	Exon 36 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.2976C>T	p.Gly992Gly	synonymous_variant	Exon 36 of 38	1		ENSP00000354228.3	Q9NY47-4
ENSG00000272104	ENST00000606589.1 link	c.128-1197G>A		intron_variant	Intron 2 of 3	3		ENSP00000476225.1	U3KQU4

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000287

AC:

AN:

240508

AF XY:

0.000325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000452

Gnomad OTH exome

AF:

0.000675

GnomAD4 exome

AF:

0.000316

AC:

461

AN:

1459558

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

242

AN XY:

726118

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33452

American (AMR)

AF:

0.000157

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51662

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000333

AC:

370

AN:

1111634

Other (OTH)

AF:

0.000332

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000237

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41416

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000324

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000367

Hom.:

Bravo

AF:

0.000291

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA2D2-related disorder

Benign:1

Apr 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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