chr3-50503309-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006030.4(CACNA2D2):c.115G>A(p.Gly39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 843,012 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.699

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.006458521).

BP6

Variant 3-50503309-C-T is Benign according to our data. Variant chr3-50503309-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240274.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00177 (266/150644) while in subpopulation AFR AF= 0.00627 (259/41340). AF 95% confidence interval is 0.00564. There are 3 homozygotes in gnomad4. There are 128 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 rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 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.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.-2+760G>A		intron_variant	Intron 1 of 37	1		ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

267

AN:

150534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000463

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:

0.00

Gnomad OTH

AF:

0.000482

GnomAD4 exome

AF:

0.000176

AC:

122

AN:

692368

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

332492

show subpopulations

Gnomad4 AFR exome

AF:

0.00708

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000344

Gnomad4 OTH exome

AF:

0.000353

GnomAD4 genome

AF:

0.00177

AC:

266

AN:

150644

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

128

AN XY:

73584

show subpopulations

Gnomad4 AFR

AF:

0.00627

Gnomad4 AMR

AF:

0.000396

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.0000696

Hom.:

Bravo

AF:

0.00191

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>A (p.G39R) alteration is located in exon 1 (coding exon 1) of the CACNA2D2 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the glycine (G) at amino acid position 39 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0054

.;T;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.57

T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0065

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

.;.;L;L;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.40

N;N;N;N;N

REVEL

Benign

0.020

Sift

Uncertain

0.012

D;T;D;T;D

Sift4G

Benign

0.54

T;T;T;T;T

Polyphen

0.0010, 0.0

.;.;.;B;B

Vest4

0.17

MutPred

0.27

Gain of glycosylation at P36 (P = 0.0612);Gain of glycosylation at P36 (P = 0.0612);Gain of glycosylation at P36 (P = 0.0612);Gain of glycosylation at P36 (P = 0.0612);Gain of glycosylation at P36 (P = 0.0612);

MVP

0.043

MPC

0.20

ClinPred

0.085

GERP RS

-1.2

Varity_R

0.11

gMVP

0.20

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