NM_006030.4:c.270C>T

Variant names:

• chr3-50476136-G-A
• rs754832829
• NM_006030.4:c.270C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_006030.4(CACNA2D2):​c.270C>T​(p.Gly90Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000761 in 1,602,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.98
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-50476136-G-A is Benign according to our data. Variant chr3-50476136-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 461316.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.98 with no splicing effect.

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.270C>T	p.Gly90Gly	synonymous	Exon 2 of 38	NP_006021.2
	CACNA2D2	NM_001174051.3		c.270C>T	p.Gly90Gly	synonymous	Exon 2 of 39	NP_001167522.1
	CACNA2D2	NM_001005505.3		c.270C>T	p.Gly90Gly	synonymous	Exon 2 of 38	NP_001005505.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.270C>T	p.Gly90Gly	synonymous	Exon 2 of 38	ENSP00000390329.2
	CACNA2D2	ENST00000423994.6	TSL:5	c.270C>T	p.Gly90Gly	synonymous	Exon 2 of 39	ENSP00000407393.2
	CACNA2D2	ENST00000479441.1	TSL:1	c.270C>T	p.Gly90Gly	synonymous	Exon 2 of 39	ENSP00000418081.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000954 AC: 22 AN: 230724 AF XY: 0.000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000752 AC: 109 AN: 1450066 Hom.: 0 Cov.: 30 AF XY: 0.0000764 AC XY: 55 AN XY: 720330

African (AFR) AF: 0.000120 AC: 4 AN: 33312

American (AMR) AF: 0.0000228 AC: 1 AN: 43846

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.000155 AC: 13 AN: 84102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000804 AC: 89 AN: 1106902

Other (OTH) AF: 0.0000167 AC: 1 AN: 59966

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.0000869

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.98
DANN	Benign	0.87
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs754832829; hg19: chr3-50513567; COSMIC: COSV56560507;