rs569543350

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_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. 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 0.024 ( 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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

cerebellar atrophy with seizures and variable developmental delay
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
complex neurodevelopmental disorder
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

CACNA2D2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

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 VariationId is 252556.

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 rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.160C>T	p.Leu54Phe	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.160C>T	p.Leu54Phe	missense_variant	Exon 1 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.160C>T	p.Leu54Phe	missense_variant	Exon 1 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.160C>T	p.Leu54Phe	missense_variant	Exon 1 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.-2+805C>T		intron_variant	Intron 1 of 37	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

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.00232

AC:

2409

AN:

1038044

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1076

AN XY:

489892

show subpopulations

African (AFR)

AF:

0.0813

AC:

1736

AN:

21340

American (AMR)

AF:

0.00729

AC:

AN:

7136

Ashkenazi Jewish (ASJ)

AF:

0.00422

AC:

AN:

12558

East Asian (EAS)

AF:

0.00

AC:

AN:

23416

South Asian (SAS)

AF:

0.000262

AC:

AN:

19106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19994

Middle Eastern (MID)

AF:

0.00483

AC:

AN:

2690

European-Non Finnish (NFE)

AF:

0.000327

AC:

291

AN:

891212

Other (OTH)

AF:

0.00638

AC:

259

AN:

40592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

188

282

376

470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0241

AC:

3656

AN:

151530

Hom.:

163

Cov.:

AF XY:

0.0234

AC XY:

1735

AN XY:

74052

show subpopulations

African (AFR)

AF:

0.0826

AC:

3420

AN:

41428

American (AMR)

AF:

0.0101

AC:

154

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10332

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000472

AC:

AN:

67794

Other (OTH)

AF:

0.0152

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Aug 24, 2015

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebellar atrophy with seizures and variable developmental delay

Uncertain:1

Oct 11, 2019

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA2D2-related disorder

Benign:1

Apr 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.6

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

PromoterAI

0.0047

Neutral

(source)

Varity_R

0.090

gMVP

0.11

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over