rs569543350

Positions:

• chr3-50503264-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The NM_006030.4(CACNA2D2):​c.160C>T​(p.Leu54Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,189,574 control chromosomes in the GnomAD database, including 240 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (163 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (77 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA2D2
• BP4: Computational evidence support a benign effect (MetaRNN=0.003566891).
• BP6: Variant 3-50503264-G-A is Benign according to our data. Variant chr3-50503264-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252556.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4	c.160C>T	p.Leu54Phe	missense_variant	1/38	ENST00000424201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.160C>T	p.Leu54Phe	missense_variant	1/38	1	NM_006030.4	P4

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3643 AN: 151422 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0824

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000472

Gnomad OTH AF: 0.0154

GnomAD4 exome AF: 0.00232 AC: 2409 AN: 1038044 Hom.: 77 Cov.: 24 AF XY: 0.00220 AC XY: 1076 AN XY: 489892

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.00422

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000262

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.00638

GnomAD4 genome AF: 0.0241 AC: 3656 AN: 151530 Hom.: 163 Cov.: 32 AF XY: 0.0234 AC XY: 1735 AN XY: 74052

Gnomad4 AFR AF: 0.0826

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000472

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0192 Hom.: 12

Bravo AF: 0.0284

ExAC AF: 0.000128 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Aug 24, 2015

- -

Cerebellar atrophy with seizures and variable developmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 11, 2019

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

CACNA2D2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

This variant is classified as 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	0.087
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.0017
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.52	T;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.47	N;N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.077	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.91, 0.86	.;.;.;P;P
Vest4		0.20
MVP		0.068
MPC		0.18
ClinPred		0.42	T
GERP RS		3.4
Varity_R		0.090
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs569543350; hg19: chr3-50540695; COSMIC: COSV56566684;