rs41291734

Positions:

chr3-50476182-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA2D2. . Gene score misZ 2.9999 (greater than the threshold 3.09). Trascript score misZ 3.123 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar atrophy with seizures and variable developmental delay, complex neurodevelopmental disorder.

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 id is 218531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-50476182-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 linkuse as main transcript	c.224G>A	p.Arg75Gln	missense_variant	2/38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7 linkuse as main transcript	c.224G>A	p.Arg75Gln	missense_variant	2/38	1	NM_006030.4	ENSP00000390329	P4	Q9NY47-2

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

GnomAD3 exomes

AF:

0.0181

AC:

3933

AN:

217570

Hom.:

AF XY:

0.0185

AC XY:

2174

AN XY:

117666

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 SAS exome

AF:

0.00410

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

Gnomad4 AFR exome

AF:

0.00413

Gnomad4 AMR exome

AF:

0.00607

Gnomad4 ASJ exome

AF:

0.00368

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00455

Gnomad4 FIN exome

AF:

0.0302

Gnomad4 NFE exome

AF:

0.0337

Gnomad4 OTH exome

AF:

0.0217

GnomAD4 genome

AF:

0.0189

AC:

2886

AN:

152322

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1335

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00637

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0279

Gnomad4 NFE

AF:

0.0309

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0264

Hom.:

100

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 16, 2015

- -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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

MutationTaster

Benign

0.64

D;D;D;D;D;D;D;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over