3-50378998-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

CACNA2D2 Gene-Disease associations (from GenCC):

• cerebellar atrophy with seizures and variable developmental delay

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 416539.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 = 0.00166 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006030.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	NM_006030.4	MANE Select	c.1261-5C>A		splice_region intron	N/A	NP_006021.2
	CACNA2D2	NM_001174051.3		c.1261-5C>A		splice_region intron	N/A	NP_001167522.1
	CACNA2D2	NM_001005505.3		c.1261-5C>A		splice_region intron	N/A	NP_001005505.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.1261-5C>A		splice_region intron	N/A	ENSP00000390329.2
	CACNA2D2	ENST00000423994.6	TSL:5	c.1261-5C>A		splice_region intron	N/A	ENSP00000407393.2
	CACNA2D2	ENST00000479441.1	TSL:1	c.1261-5C>A		splice_region intron	N/A	ENSP00000418081.1

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

GnomAD2 exomes AF: 0.00164 AC: 411 AN: 250956 AF XY: 0.00178

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 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

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86256

European-Finnish (FIN) AF: 0.000752 AC: 40 AN: 53162

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00368 AC: 4091 AN: 1111994

Other (OTH) AF: 0.00194 AC: 117 AN: 60390

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

African (AFR) AF: 0.000722 AC: 30 AN: 41580

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

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

Developmental and epileptic encephalopathy 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.66
PhyloP100		-0.093
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs201656322; hg19: chr3-50416429;