rs150832847

Variant names:

• chr3-50364700-G-A
• rs150832847
• NM_006030.4:c.3398C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006030.4(CACNA2D2):​c.3398C>T​(p.Pro1133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,544,380 control chromosomes in the GnomAD database, including 14 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1133S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (13 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.64
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029498637).
• BP6: Variant 3-50364700-G-A is Benign according to our data. Variant chr3-50364700-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0019 (289/152322) while in subpopulation NFE AF = 0.00316 (215/68024). AF 95% confidence interval is 0.00281. There are 1 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

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.3398C>T	p.Pro1133Leu	missense	Exon 38 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.3419C>T	p.Pro1140Leu	missense	Exon 39 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.3404C>T	p.Pro1135Leu	missense	Exon 38 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.3398C>T	p.Pro1133Leu	missense	Exon 38 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3428C>T	p.Pro1143Leu	missense	Exon 39 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000479441.1	TSL:1	c.3419C>T	p.Pro1140Leu	missense	Exon 39 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00160 AC: 245 AN: 153562 AF XY: 0.00172

Gnomad AFR exome AF: 0.000358

Gnomad AMR exome AF: 0.000505

Gnomad ASJ exome AF: 0.00425

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000652

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.00306 AC: 4265 AN: 1392058 Hom.: 13 Cov.: 33 AF XY: 0.00302 AC XY: 2071 AN XY: 686170

African (AFR) AF: 0.000384 AC: 12 AN: 31260

American (AMR) AF: 0.000809 AC: 28 AN: 34608

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 81 AN: 24916

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35648

South Asian (SAS) AF: 0.000669 AC: 53 AN: 79208

European-Finnish (FIN) AF: 0.000124 AC: 6 AN: 48310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4350

European-Non Finnish (NFE) AF: 0.00366 AC: 3935 AN: 1076170

Other (OTH) AF: 0.00259 AC: 149 AN: 57588

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74484

African (AFR) AF: 0.000673 AC: 28 AN: 41582

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00316 AC: 215 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00212

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000717 AC: 3

ESP6500EA AF: 0.00218 AC: 18

ExAC AF: 0.000902 AC: 96

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CACNA2D2-related disorder (1)
-	-	1	Cerebellar atrophy with seizures and variable developmental delay (1)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.053
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.075
MVP		0.043
MPC		1.3
ClinPred		0.040	T
GERP RS		2.8
Varity_R		0.059
gMVP		0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150832847; hg19: chr3-50402131;