rs772333671

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.44

Variant links:

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 links:

LOC127898564 (HGNC:):

LOC127898564 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.3203C>T	p.Thr1068Met	missense_variant	36/38	ENST00000424201.7	NP_006021.2
LOC127898564	NR_183066.1 linkuse as main transcript	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 linkuse as main transcript	c.3203C>T	p.Thr1068Met	missense_variant	36/38	1	NM_006030.4	ENSP00000390329	P4	Q9NY47-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239114

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131876

show subpopulations

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:

AN:

1458848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725782

show subpopulations

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.:

ExAC

AF:

0.00000836

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0063

.;T;.;.;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.56

T;D;T;T;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

.;.;.;.;.;L

MutationTaster

Benign

0.60

N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over