rs148079551

Variant names:

• chr3-50365419-T-C
• rs148079551
• NM_006030.4:c.3035A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_006030.4(CACNA2D2):​c.3035A>G​(p.Gln1012Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.61
• Publications: 3 publications found

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

ENSG00000272104 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006030.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	NM_006030.4	MANE Select	c.3035A>G	p.Gln1012Arg	missense	Exon 35 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.3056A>G	p.Gln1019Arg	missense	Exon 36 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.3035A>G	p.Gln1012Arg	missense	Exon 35 of 38	NP_001005505.1	Q9NY47-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.3035A>G	p.Gln1012Arg	missense	Exon 35 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3059A>G	p.Gln1020Arg	missense	Exon 36 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000479441.1	TSL:1	c.3056A>G	p.Gln1019Arg	missense	Exon 36 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000920 AC: 23 AN: 249868 AF XY: 0.0000738

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461360 Hom.: 0 Cov.: 36 AF XY: 0.000150 AC XY: 109 AN XY: 726976

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000193 AC: 215 AN: 1111864

Other (OTH) AF: 0.0000828 AC: 5 AN: 60376

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74354

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.023	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.63
Sift	Benign	0.14	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.63
MPC		1.4
ClinPred		0.55	D
GERP RS		5.2
Varity_R		0.66
gMVP		0.79
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs148079551; hg19: chr3-50402850;