rs5030977

Positions:

• chr3-50379070-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006030.4(CACNA2D2):​c.1260+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 1,613,318 control chromosomes in the GnomAD database, including 6,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (430 hom., cov: 33)
  • Exomes 𝑓: 0.086 (5945 hom.)
• Consequence: CACNA2D2 NM_006030.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.208

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-50379070-C-T is Benign according to our data. Variant chr3-50379070-C-T is described in ClinVar as [Benign]. Clinvar id is 1253361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.092 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.1260+22G>A		intron_variant		ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.1260+22G>A		intron_variant		1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.1260+22G>A		intron_variant		5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.1260+22G>A		intron_variant		1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1053+22G>A		intron_variant		1		ENSP00000354228.3

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9943 AN: 152170 Hom.: 431 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0940

Gnomad OTH AF: 0.0841

GnomAD3 exomes AF: 0.0722 AC: 18094 AN: 250722 Hom.: 861 AF XY: 0.0740 AC XY: 10040 AN XY: 135660

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0329

Gnomad FIN exome AF: 0.0992

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0833

GnomAD4 exome AF: 0.0864 AC: 126175 AN: 1461030 Hom.: 5945 Cov.: 32 AF XY: 0.0852 AC XY: 61956 AN XY: 726844

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.0469

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0334

Gnomad4 FIN exome AF: 0.0990

Gnomad4 NFE exome AF: 0.0965

Gnomad4 OTH exome AF: 0.0794

GnomAD4 genome AF: 0.0653 AC: 9937 AN: 152288 Hom.: 430 Cov.: 33 AF XY: 0.0640 AC XY: 4768 AN XY: 74458

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.0637

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0275

Gnomad4 FIN AF: 0.0954

Gnomad4 NFE AF: 0.0940

Gnomad4 OTH AF: 0.0828

Alfa AF: 0.0886 Hom.: 174

Bravo AF: 0.0614

Asia WGS AF: 0.0160 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.7
DANN	Benign	0.73

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: rs5030977; hg19: chr3-50416501;