rs150190044

Positions:

chr3-50476135-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_006030.4(CACNA2D2):c.271G>A(p.Val91Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000357 in 1,602,268 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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=0.009093493).

BP6

Variant 3-50476135-C-T is Benign according to our data. Variant chr3-50476135-C-T is described in ClinVar as [Benign]. Clinvar id is 416550.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00194 (295/152268) while in subpopulation AFR AF= 0.00645 (268/41564). AF 95% confidence interval is 0.00581. There are 3 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4 linkuse as main transcript	c.271G>A	p.Val91Ile	missense_variant	2/38	ENST00000424201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7 linkuse as main transcript	c.271G>A	p.Val91Ile	missense_variant	2/38	1	NM_006030.4	P4	Q9NY47-2

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

295

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000464

AC:

107

AN:

230636

Hom.:

AF XY:

0.000360

AC XY:

AN XY:

124940

show subpopulations

Gnomad AFR exome

AF:

0.00618

Gnomad AMR exome

AF:

0.000330

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000481

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000191

AC:

277

AN:

1450000

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

125

AN XY:

720274

show subpopulations

Gnomad4 AFR exome

AF:

0.00643

Gnomad4 AMR exome

AF:

0.000456

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000467

GnomAD4 genome

AF:

0.00194

AC:

295

AN:

152268

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00645

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.00241

ESP6500AA

AF:

0.00727

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000577

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.0070

.;T;.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.86

D;D;D;D;D;D

M_CAP

Benign

0.0059

MetaRNN

Benign

0.0091

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

.;.;L;.;L;L

MutationTaster

Benign

0.94

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.31

N;N;N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.40

T;T;T;T;T;T

Sift4G

Benign

0.39

T;T;T;T;T;T

Polyphen

0.59, 0.81

.;.;.;.;P;P

Vest4

0.49

MVP

0.22

MPC

0.21

ClinPred

0.013

GERP RS

5.0

Varity_R

0.051

gMVP

0.21

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