Genetic Variant CACNA2D2:p.Leu54Ile (chr3-50503264-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006030.4(CACNA2D2):c.160C>A(p.Leu54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000963 in 1,038,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L54F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.6e-7 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.60

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20598498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.160C>A	p.Leu54Ile	missense_variant	Exon 1 of 38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA2D2	ENST00000424201.7 link	c.160C>A	p.Leu54Ile	missense_variant	Exon 1 of 38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6 link	c.160C>A	p.Leu54Ile	missense_variant	Exon 1 of 39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7 link	c.160C>A	p.Leu54Ile	missense_variant	Exon 1 of 38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7 link	c.-2+805C>A		intron_variant	Intron 1 of 37	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.63e-7

AC:

AN:

1038094

Hom.:

Cov.:

AF XY:

0.00000204

AC XY:

AN XY:

489902

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21384

American (AMR)

AF:

0.00

AC:

AN:

7136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12558

East Asian (EAS)

AF:

0.00

AC:

AN:

23416

South Asian (SAS)

AF:

0.00

AC:

AN:

19106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2690

European-Non Finnish (NFE)

AF:

0.00000112

AC:

AN:

891216

Other (OTH)

AF:

0.00

AC:

AN:

40594

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0

.;T;.;.;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.092

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.57

T;T;T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;.;L;L;L

PhyloP100

1.6

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.43

N;N;N;N;N

REVEL

Benign

0.050

Sift

Uncertain

0.026

D;T;D;T;D

Sift4G

Benign

0.20

T;T;T;T;T

Vest4

0.27

ClinPred

0.38

GERP RS

3.4

PromoterAI

0.076

Neutral

(source)

Varity_R

0.13

gMVP

0.085

Mutation Taster

=88/12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over