chr3-50364700-G-A

Position:

chr3-50364700-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_006030.4(CACNA2D2):c.3398C>T(p.Pro1133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,544,380 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1133S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 13 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.64

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 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=0.0029498637).

BP6

Variant 3-50364700-G-A is Benign according to our data. Variant chr3-50364700-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0019 (289/152322) while in subpopulation NFE AF= 0.00316 (215/68024). AF 95% confidence interval is 0.00281. There are 1 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4 linkuse as main transcript	c.3398C>T	p.Pro1133Leu	missense_variant	38/38	ENST00000424201.7
LOC127898564	NR_183066.1 linkuse as main transcript	n.835-1597G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7 linkuse as main transcript	c.3398C>T	p.Pro1133Leu	missense_variant	38/38	1	NM_006030.4	P4	Q9NY47-2

Frequencies

GnomAD3 genomes

AF:

0.00190

AC:

289

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00160

AC:

245

AN:

153562

Hom.:

AF XY:

0.00172

AC XY:

140

AN XY:

81444

show subpopulations

Gnomad AFR exome

AF:

0.000358

Gnomad AMR exome

AF:

0.000505

Gnomad ASJ exome

AF:

0.00425

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000700

Gnomad FIN exome

AF:

0.0000652

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00323

GnomAD4 exome

AF:

0.00306

AC:

4265

AN:

1392058

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

2071

AN XY:

686170

show subpopulations

Gnomad4 AFR exome

AF:

0.000384

Gnomad4 AMR exome

AF:

0.000809

Gnomad4 ASJ exome

AF:

0.00325

Gnomad4 EAS exome

AF:

0.0000281

Gnomad4 SAS exome

AF:

0.000669

Gnomad4 FIN exome

AF:

0.000124

Gnomad4 NFE exome

AF:

0.00366

Gnomad4 OTH exome

AF:

0.00259

GnomAD4 genome

AF:

0.00190

AC:

289

AN:

152322

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00256

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000717

AC:

ESP6500EA

AF:

0.00218

AC:

ExAC

AF:

0.000902

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	CACNA2D2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 18, 2020	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Cerebellar atrophy with seizures and variable developmental delay

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jan 12, 2022

CACNA2D2 NM_006030.3 exon 38 p.Pro1133Leu (c.3398C>T): This variant has not been reported in the literature but is present in 0.3% (209/64570) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-50364700-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:240279). This variant amino acid (Leu) is present in several species, including the platypus and several non-mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. However, additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

CACNA2D2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

.;T;.;.;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.77

T;T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;.;.;N

MutationTaster

Benign

0.98

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

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.56

N;N;N;N;N;N

REVEL

Benign

0.053

Sift

Benign

0.11

T;T;T;D;T;T

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.0

.;.;.;.;B;B

Vest4

0.075

MVP

0.043

MPC

1.3

ClinPred

0.040

GERP RS

2.8

Varity_R

0.059

gMVP

0.68

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