rs5030977

Variant names:

• chr3-50379070-C-T
• rs5030977
• NM_006030.4:c.1260+22G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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=-0.83).
• BP6: Variant 3-50379070-C-T is Benign according to our data. Variant chr3-50379070-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.1260+22G>A		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.1260+22G>A		intron_variant	Intron 12 of 37	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.1260+22G>A		intron_variant	Intron 12 of 38	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.1260+22G>A		intron_variant	Intron 12 of 37	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1053+22G>A		intron_variant	Intron 12 of 37	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

GnomAD2 exomes AF: 0.0722 AC: 18094 AN: 250722 AF XY: 0.0740

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 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

African (AFR) AF: 0.0125 AC: 419 AN: 33470

American (AMR) AF: 0.0469 AC: 2098 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3046 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0334 AC: 2880 AN: 86242

European-Finnish (FIN) AF: 0.0990 AC: 5267 AN: 53224

Middle Eastern (MID) AF: 0.0749 AC: 432 AN: 5768

European-Non Finnish (NFE) AF: 0.0965 AC: 107239 AN: 1111418

Other (OTH) AF: 0.0794 AC: 4791 AN: 60366

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

African (AFR) AF: 0.0162 AC: 673 AN: 41560

American (AMR) AF: 0.0637 AC: 975 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4832

European-Finnish (FIN) AF: 0.0954 AC: 1012 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0940 AC: 6390 AN: 68004

Other (OTH) AF: 0.0828 AC: 175 AN: 2114

Alfa AF: 0.0914 Hom.: 323

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.7
DANN	Benign	0.73
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5030977; hg19: chr3-50416501;