rs2239801

Variant names:

• chr3-50364878-C-G
• rs2239801
• NM_006030.4:c.3291+10G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-50364878-C-G
• chr3-50364878-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001174051.3(CACNA2D2):​c.3312+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,314 control chromosomes in the GnomAD database, including 9,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (621 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8810 hom.)
• Consequence: CACNA2D2 NM_001174051.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.11
• Publications: 14 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

ENSG00000272104 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-50364878-C-G is Benign according to our data. Variant chr3-50364878-C-G is described in ClinVar as Benign. ClinVar VariationId is 585338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174051.3. 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.3291+10G>C		intron	N/A	NP_006021.2
	CACNA2D2	NM_001174051.3		c.3312+10G>C		intron	N/A	NP_001167522.1
	CACNA2D2	NM_001005505.3		c.3297+10G>C		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.3291+10G>C		intron	N/A	ENSP00000390329.2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3321+10G>C		intron	N/A	ENSP00000407393.2
	CACNA2D2	ENST00000479441.1	TSL:1	c.3312+10G>C		intron	N/A	ENSP00000418081.1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12452 AN: 152152 Hom.: 618 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.0735

Gnomad EAS AF: 0.0572

Gnomad SAS AF: 0.0957

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0875

GnomAD2 exomes AF: 0.0963 AC: 23966 AN: 248880 AF XY: 0.0989

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0721

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.0567

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.108 AC: 157503 AN: 1461044 Hom.: 8810 Cov.: 35 AF XY: 0.108 AC XY: 78687 AN XY: 726834

African (AFR) AF: 0.0221 AC: 740 AN: 33472

American (AMR) AF: 0.0734 AC: 3284 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 1981 AN: 26126

East Asian (EAS) AF: 0.0792 AC: 3145 AN: 39690

South Asian (SAS) AF: 0.104 AC: 8972 AN: 86256

European-Finnish (FIN) AF: 0.145 AC: 7680 AN: 52796

Middle Eastern (MID) AF: 0.102 AC: 589 AN: 5764

European-Non Finnish (NFE) AF: 0.112 AC: 124772 AN: 1111856

Other (OTH) AF: 0.105 AC: 6340 AN: 60370

GnomAD4 genome AF: 0.0818 AC: 12456 AN: 152270 Hom.: 621 Cov.: 32 AF XY: 0.0822 AC XY: 6118 AN XY: 74440

African (AFR) AF: 0.0253 AC: 1050 AN: 41566

American (AMR) AF: 0.0740 AC: 1133 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0735 AC: 255 AN: 3470

East Asian (EAS) AF: 0.0570 AC: 295 AN: 5176

South Asian (SAS) AF: 0.0960 AC: 463 AN: 4824

European-Finnish (FIN) AF: 0.141 AC: 1494 AN: 10602

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7371 AN: 68008

Other (OTH) AF: 0.0903 AC: 191 AN: 2114

Alfa AF: 0.0942 Hom.: 139

Bravo AF: 0.0746

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.54
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs2239801; hg19: chr3-50402309; COSMIC: COSV56561717; COSMIC: COSV56561717;