NM_006030.4:c.146C>G

Variant names:

• chr3-50503278-G-C
• rs951683514
• NM_006030.4:c.146C>G

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.146C>G​(p.Pro49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 1,014,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P49S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.115
• 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: 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=0.1016548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.146C>G	p.Pro49Arg	missense_variant	Exon 1 of 38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.146C>G	p.Pro49Arg	missense_variant	Exon 1 of 38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.146C>G	p.Pro49Arg	missense_variant	Exon 1 of 39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.146C>G	p.Pro49Arg	missense_variant	Exon 1 of 38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.-2+791C>G		intron_variant	Intron 1 of 37	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000197 AC: 2 AN: 1014684 Hom.: 0 Cov.: 19 AF XY: 0.00000417 AC XY: 2 AN XY: 479410

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20824

American (AMR) AF: 0.00 AC: 0 AN: 6998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12290

East Asian (EAS) AF: 0.00 AC: 0 AN: 22930

South Asian (SAS) AF: 0.0000535 AC: 1 AN: 18680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2644

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 870906

Other (OTH) AF: 0.00 AC: 0 AN: 39598

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 49 of the CACNA2D2 protein (p.Pro49Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.0035	.;T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.26	T;T;T;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	.;.;N;N;N
PhyloP100		0.12
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.030	N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.031, 0.018	.;.;.;B;B
Vest4		0.33
MutPred		0.45		Gain of MoRF binding (P = 0.0133);Gain of MoRF binding (P = 0.0133);Gain of MoRF binding (P = 0.0133);Gain of MoRF binding (P = 0.0133);Gain of MoRF binding (P = 0.0133);
MVP		0.52
MPC		0.18
ClinPred		0.046	T
GERP RS		-0.95
PromoterAI		-0.0022	Neutral
Varity_R		0.078
gMVP		0.22
Mutation Taster		=98/2	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: rs951683514; hg19: chr3-50540709;