chr3-50365080-G-A

Position:

• chr3-50365080-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006030.4(CACNA2D2):​c.3203C>T​(p.Thr1068Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.44

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]

LOC127898564 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA2D2. . Gene score misZ 2.9999 (greater than the threshold 3.09). Trascript score misZ 3.123 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar atrophy with seizures and variable developmental delay, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27201504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.3203C>T	p.Thr1068Met	missense_variant	36/38	ENST00000424201.7	NP_006021.2
LOC127898564	NR_183066.1	n.835-1217G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.3203C>T	p.Thr1068Met	missense_variant	36/38	1	NM_006030.4	ENSP00000390329	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 239114 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131876

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 SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458848 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 21, 2023

Variant summary: CACNA2D2 c.3203C>T (p.Thr1068Met) results in a non-conservative amino acid change located in the Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region (IPR013680) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 239114 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3203C>T in individuals affected with Cerebellar Atrophy With Seizures And Variable Developmental Delay and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 28, 2019

In summary, this variant has uncertain impact on CACNA2D2 function. The available evidence is currently insufficient to determine its role 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a CACNA2D2-related disease. ClinVar contains an entry for this variant (Variation ID: 426206). This variant is present in population databases (rs772333671, ExAC 0.006%). This sequence change replaces threonine with methionine at codon 1068 of the CACNA2D2 protein (p.Thr1068Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2017

The T1068M variant in the CACNA2D2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T1068M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1068M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T1068M as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0063	.;T;.;.;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.56	T;D;T;T;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	.;.;.;.;.;L
MutationTaster	Benign	0.60	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.069	T;T;T;D;T;T
Sift4G	Benign	0.075	T;D;T;T;D;D
Polyphen		0.97, 0.94	.;.;.;.;D;P
Vest4		0.46
MutPred		0.19		.;.;.;.;.;Loss of phosphorylation at T1075 (P = 0.0959);
MVP		0.17
MPC		0.89
ClinPred		0.63	D
GERP RS		3.6
Varity_R		0.049
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772333671; hg19: chr3-50402511;