chr3-50364712-G-A

Variant names:

• chr3-50364712-G-A
• rs1014755697
• NM_006030.4:c.3386C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006030.4(CACNA2D2):​c.3386C>T​(p.Pro1129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,547,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1129P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000272104 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1067166).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	NM_006030.4	MANE Select	c.3386C>T	p.Pro1129Leu	missense	Exon 38 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.3407C>T	p.Pro1136Leu	missense	Exon 39 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.3392C>T	p.Pro1131Leu	missense	Exon 38 of 38	NP_001005505.1	Q9NY47-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.3386C>T	p.Pro1129Leu	missense	Exon 38 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3416C>T	p.Pro1139Leu	missense	Exon 39 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000479441.1	TSL:1	c.3407C>T	p.Pro1136Leu	missense	Exon 39 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395448 Hom.: 0 Cov.: 33 AF XY: 0.00000291 AC XY: 2 AN XY: 688368

African (AFR) AF: 0.0000319 AC: 1 AN: 31362

American (AMR) AF: 0.00 AC: 0 AN: 34946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25042

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4472

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078052

Other (OTH) AF: 0.00 AC: 0 AN: 57750

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.063
Sift	Benign	0.034	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.083
MutPred		0.29		Loss of glycosylation at P1139 (P = 0.0053)
MVP		0.043
MPC		1.3
ClinPred		0.53	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.74
Mutation Taster		=97/3	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: rs1014755697; hg19: chr3-50402143;