rs757572722

Positions:

chr3-50365125-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting

The NM_006030.4(CACNA2D2):c.3158C>T(p.Pro1053Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,612,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

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:

LOC127898564 (HGNC:):

LOC127898564 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.07917899).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000263 (4/152262) while in subpopulation AMR AF= 0.000196 (3/15306). AF 95% confidence interval is 0.0000528. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 linkuse as main transcript	c.3158C>T	p.Pro1053Leu	missense_variant	36/38	ENST00000424201.7	NP_006021.2
LOC127898564	NR_183066.1 linkuse as main transcript	n.835-1172G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7 linkuse as main transcript	c.3158C>T	p.Pro1053Leu	missense_variant	36/38	1	NM_006030.4	ENSP00000390329	P4	Q9NY47-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

GnomAD3 exomes

AF:

0.0000539

AC:

AN:

241282

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

132890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000935

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1459878

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000669

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1053 of the CACNA2D2 protein (p.Pro1053Leu). This variant is present in population databases (rs757572722, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 530507). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.012

.;T;.;.;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.011

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.079

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.26

.;.;.;.;.;N

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.0

N;N;N;N;N;N

REVEL

Benign

0.081

Sift

Benign

0.23

T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T

Polyphen

0.0020, 0.0010

.;.;.;.;B;B

Vest4

0.33

MutPred

0.42

.;.;.;.;.;Loss of methylation at K1059 (P = 0.0656);

MVP

0.12

MPC

0.49

ClinPred

0.081

GERP RS

4.7

Varity_R

0.10

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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