3-50503304-G-A

Variant names:

• chr3-50503304-G-A
• rs907775113
• NM_006030.4:c.120C>T

Variant summary

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

The ENST00000266039.7(CACNA2D2):​c.120C>T​(p.Pro40Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 904,544 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CACNA2D2 ENST00000266039.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.79
• 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=-0.64).
• BP6: Variant 3-50503304-G-A is Benign according to our data. Variant chr3-50503304-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 530582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000266039.7. 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.120C>T	p.Pro40Pro	synonymous	Exon 1 of 38	NP_006021.2
	CACNA2D2	NM_001174051.3		c.120C>T	p.Pro40Pro	synonymous	Exon 1 of 39	NP_001167522.1
	CACNA2D2	NM_001005505.3		c.120C>T	p.Pro40Pro	synonymous	Exon 1 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.120C>T	p.Pro40Pro	synonymous	Exon 1 of 38	ENSP00000390329.2
	CACNA2D2	ENST00000423994.6	TSL:5	c.120C>T	p.Pro40Pro	synonymous	Exon 1 of 39	ENSP00000407393.2
	CACNA2D2	ENST00000479441.1	TSL:1	c.120C>T	p.Pro40Pro	synonymous	Exon 1 of 39	ENSP00000418081.1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150842 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 86 AN: 753702 Hom.: 0 Cov.: 10 AF XY: 0.000116 AC XY: 42 AN XY: 360828

African (AFR) AF: 0.00 AC: 0 AN: 15348

American (AMR) AF: 0.00 AC: 0 AN: 6316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10232

East Asian (EAS) AF: 0.00 AC: 0 AN: 20722

South Asian (SAS) AF: 0.00 AC: 0 AN: 13652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2114

European-Non Finnish (NFE) AF: 0.000135 AC: 86 AN: 635762

Other (OTH) AF: 0.00 AC: 0 AN: 30524

GnomAD4 genome AF: 0.0000464 AC: 7 AN: 150842 Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 3 AN XY: 73628

African (AFR) AF: 0.00 AC: 0 AN: 41302

American (AMR) AF: 0.00 AC: 0 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67614

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CACNA2D2-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.9
DANN	Benign	0.92
PhyloP100		1.8
PromoterAI		0.090	Neutral
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: rs907775113; hg19: chr3-50540735;