dbSNP rs41291734: CACNA2D2:p.Arg75Pro (chr3-50476182-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006030.4(CACNA2D2):c.224G>C(p.Arg75Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,442,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R75W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.26

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.224G>C	p.Arg75Pro	missense_variant	Exon 2 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.224G>C	p.Arg75Pro	missense_variant	Exon 2 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.224G>C	p.Arg75Pro	missense_variant	Exon 2 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.224G>C	p.Arg75Pro	missense_variant	Exon 2 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.17G>C	p.Arg6Pro	missense_variant	Exon 2 of 38	1		ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1442342

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715834

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33148

American (AMR)

AF:

0.00

AC:

AN:

43014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

38930

South Asian (SAS)

AF:

0.00

AC:

AN:

83350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103474

Other (OTH)

AF:

0.00

AC:

AN:

59658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Pathogenic

0.90

BayesDel_addAF

Benign

-0.0032

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

.;T;.;.;.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.65

D;D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.7

.;.;L;.;L;L

PhyloP100

4.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.79

N;N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.10

T;T;T;D;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

0.99, 0.99

.;.;.;.;D;D

Vest4

0.80

MutPred

0.49

Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);.;Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);

MVP

0.13

MPC

0.63

ClinPred

0.86

GERP RS

5.0

Varity_R

0.50

gMVP

0.78

Mutation Taster

=65/35

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