rs569543350

Positions:

chr3-50503264-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BA1

The NM_006030.4(CACNA2D2):c.160C>T(p.Leu54Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,189,574 control chromosomes in the GnomAD database, including 240 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.024 ( 163 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 77 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.60

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:

CACNA2D2 (HGNC:):

CACNA2D2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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=0.003566891).

BP6

Variant 3-50503264-G-A is Benign according to our data. Variant chr3-50503264-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252556.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 linkuse as main transcript	c.160C>T	p.Leu54Phe	missense_variant	1/38	ENST00000424201.7	NP_006021.2	Q9NY47-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA2D2	ENST00000424201.7 linkuse as main transcript	c.160C>T	p.Leu54Phe	missense_variant	1/38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 linkuse as main transcript	c.160C>T	p.Leu54Phe	missense_variant	1/39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 linkuse as main transcript	c.160C>T	p.Leu54Phe	missense_variant	1/38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 linkuse as main transcript	c.-2+805C>T		intron_variant		1		ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes

AF:

0.0241

AC:

3643

AN:

151422

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0824

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000472

Gnomad OTH

AF:

0.0154

GnomAD4 exome

AF:

0.00232

AC:

2409

AN:

1038044

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1076

AN XY:

489892

show subpopulations

Gnomad4 AFR exome

AF:

0.0813

Gnomad4 AMR exome

AF:

0.00729

Gnomad4 ASJ exome

AF:

0.00422

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000262

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000327

Gnomad4 OTH exome

AF:

0.00638

GnomAD4 genome

AF:

0.0241

AC:

3656

AN:

151530

Hom.:

163

Cov.:

AF XY:

0.0234

AC XY:

1735

AN XY:

74052

show subpopulations

Gnomad4 AFR

AF:

0.0826

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000472

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0192

Hom.:

Bravo

AF:

0.0284

ExAC

AF:

0.000128

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 24, 2015

- -

Cerebellar atrophy with seizures and variable developmental delay

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 11, 2019

- -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

CACNA2D2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

This variant is classified as 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

0.087

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.010

.;T;.;.;T

Eigen

Benign

-0.0017

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.52

T;T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;.;L;L;L

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.47

N;N;N;N;N

REVEL

Benign

0.056

Sift

Benign

0.077

T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

0.91, 0.86

.;.;.;P;P

Vest4

0.20

MVP

0.068

MPC

0.18

ClinPred

0.42

GERP RS

3.4

Varity_R

0.090

gMVP

0.11

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