3-50364700-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 12/20 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

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]

LOC127898564 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA2D2
• 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4	c.3398C>T	p.Pro1133Leu	missense_variant	38/38	ENST00000424201.7
LOC127898564	NR_183066.1	n.835-1597G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.3398C>T	p.Pro1133Leu	missense_variant	38/38	1	NM_006030.4	P4

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

GnomAD3 exomes AF: 0.00160 AC: 245 AN: 153562 Hom.: 2 AF XY: 0.00172 AC XY: 140 AN XY: 81444

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 SAS exome AF: 0.000700

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

Gnomad4 AFR exome AF: 0.000384

Gnomad4 AMR exome AF: 0.000809

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.000669

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.00366

Gnomad4 OTH exome AF: 0.00259

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

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00236

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	CACNA2D2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 18, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Cerebellar atrophy with seizures and variable developmental delay Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jan 12, 2022

CACNA2D2 NM_006030.3 exon 38 p.Pro1133Leu (c.3398C>T): This variant has not been reported in the literature but is present in 0.3% (209/64570) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-50364700-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:240279). This variant amino acid (Leu) is present in several species, including the platypus and several non-mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. However, additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

CACNA2D2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.77	T;T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.11	T;T;T;D;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.0	.;.;.;.;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs150832847; hg19: chr3-50402131;