3-50378998-G-T

Variant names:

• chr3-50378998-G-T
• rs201656322
• NM_006030.4:c.1261-5C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006030.4(CACNA2D2):​c.1261-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,916 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: CACNA2D2 NM_006030.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006993
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930

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=-0.78).
• BP6: Variant 3-50378998-G-T is Benign according to our data. Variant chr3-50378998-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 416539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-50378998-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00166 (253/152310) while in subpopulation NFE AF= 0.00291 (198/68018). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.1261-5C>A		splice_region_variant, intron_variant	Intron 12 of 37	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.1261-5C>A		splice_region_variant, intron_variant	Intron 12 of 37	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.1261-5C>A		splice_region_variant, intron_variant	Intron 12 of 38	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.1261-5C>A		splice_region_variant, intron_variant	Intron 12 of 37	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1054-5C>A		splice_region_variant, intron_variant	Intron 12 of 37	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00164 AC: 411 AN: 250956 Hom.: 0 AF XY: 0.00178 AC XY: 242 AN XY: 135826

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00300 AC: 4387 AN: 1461606 Hom.: 10 Cov.: 33 AF XY: 0.00298 AC XY: 2164 AN XY: 727076

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.000752

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74478

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00291

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00192 Hom.: 0

Bravo AF: 0.00165

EpiCase AF: 0.00180

EpiControl AF: 0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA2D2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.098
SpliceAI score (max)		0.060		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: rs201656322; hg19: chr3-50416429;