dbSNP rs371214569: CACNA2D2:p.Arg616Met (chr3-50375704-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006030.4(CACNA2D2):c.1847G>T(p.Arg616Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000479 in 1,461,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 missense, splice_region

Scores

Splicing: ADA: 0.8170

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.70

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.1847G>T	p.Arg616Met	missense_variant, splice_region_variant	Exon 21 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.1847G>T	p.Arg616Met	missense_variant, splice_region_variant	Exon 21 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.1847G>T	p.Arg616Met	missense_variant, splice_region_variant	Exon 21 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.1847G>T	p.Arg616Met	missense_variant, splice_region_variant	Exon 21 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.1640G>T	p.Arg547Met	missense_variant, splice_region_variant	Exon 21 of 38	1		ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461084

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.16

.;T;.;.;.;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.4

.;.;M;.;M;M

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

0.81, 0.99

.;.;.;.;P;D

Vest4

0.69

MutPred

0.76

Gain of catalytic residue at R616 (P = 0.0363);Gain of catalytic residue at R616 (P = 0.0363);Gain of catalytic residue at R616 (P = 0.0363);.;Gain of catalytic residue at R616 (P = 0.0363);Gain of catalytic residue at R616 (P = 0.0363);

MVP

0.44

MPC

1.4

ClinPred

0.99

GERP RS

4.7

Varity_R

0.30

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over