3-50364696-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

The NM_006030.4(CACNA2D2):c.3402A>C(p.Gln1134His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,543,274 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1134Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.07

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA2D2
• BP4: Computational evidence support a benign effect (MetaRNN=0.013061792).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00126 (192/152212) while in subpopulation AMR AF= 0.00327 (50/15298). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D2	NM_006030.4	c.3402A>C	p.Gln1134His	missense_variant	38/38	ENST00000424201.7
LOC127898564	NR_183066.1	n.835-1601T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.3402A>C	p.Gln1134His	missense_variant	38/38	1	NM_006030.4	P4

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00121 AC: 186 AN: 153644 Hom.: 0 AF XY: 0.00145 AC XY: 118 AN XY: 81362

Gnomad AFR exome AF: 0.000236

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.000694

GnomAD4 exome AF: 0.00149 AC: 2069 AN: 1391062 Hom.: 2 Cov.: 32 AF XY: 0.00150 AC XY: 1028 AN XY: 685470

Gnomad4 AFR exome AF: 0.000256

Gnomad4 AMR exome AF: 0.000925

Gnomad4 ASJ exome AF: 0.0000402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.000538

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74418

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00113

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00182 AC: 15

ExAC AF: 0.000558 AC: 59

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1134 of the CACNA2D2 protein (p.Gln1134His). This variant is present in population databases (rs150284749, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411013). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Dec 30, 2021

BP4, PP2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.61	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.060	T;T;T;T;T;T
Polyphen		0.92, 0.88	.;.;.;.;P;P
Vest4		0.18
MutPred		0.14		Gain of loop (P = 0.069);.;.;.;.;.;
MVP		0.12
MPC		0.76
ClinPred		0.077	T
GERP RS		3.1
Varity_R		0.18
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs150284749; hg19: chr3-50402127;