chr3-50364705-C-T

Position:

• chr3-50364705-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006030.4(CACNA2D2):​c.3393G>A​(p.Pro1131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000989 in 1,544,338 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: CACNA2D2 NM_006030.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.07

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-50364705-C-T is Benign according to our data. Variant chr3-50364705-C-T is described in ClinVar as [Benign]. Clinvar id is 240278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00512 (780/152274) while in subpopulation AFR AF= 0.0175 (726/41566). AF 95% confidence interval is 0.0164. There are 10 homozygotes in gnomad4. There are 358 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4	c.3393G>A	p.Pro1131=	synonymous_variant	38/38	ENST00000424201.7
LOC127898564	NR_183066.1	n.835-1592C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.3393G>A	p.Pro1131=	synonymous_variant	38/38	1	NM_006030.4	P4

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 775 AN: 152156 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00124 AC: 190 AN: 152734 Hom.: 1 AF XY: 0.00103 AC XY: 84 AN XY: 81172

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000875

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000338

Gnomad OTH exome AF: 0.000462

GnomAD4 exome AF: 0.000537 AC: 747 AN: 1392064 Hom.: 4 Cov.: 33 AF XY: 0.000528 AC XY: 362 AN XY: 686250

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000757

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000660

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152274 Hom.: 10 Cov.: 33 AF XY: 0.00481 AC XY: 358 AN XY: 74460

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.00582

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Athena Diagnostics	Dec 08, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 20, 2017

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.8
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145772306; hg19: chr3-50402136;