3-50367892-G-T

Variant names:

• chr3-50367892-G-T
• rs753131879
• NM_006030.4:c.2154C>A

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.2154C>A​(p.Phe718Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 747,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F718F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• 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

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=0.13900545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.2154C>A	p.Phe718Leu	missense_variant	Exon 25 of 38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.2154C>A	p.Phe718Leu	missense_variant	Exon 25 of 38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.2175C>A	p.Phe725Leu	missense_variant	Exon 26 of 39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.2154C>A	p.Phe718Leu	missense_variant	Exon 25 of 38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1947C>A	p.Phe649Leu	missense_variant	Exon 25 of 38	1		ENSP00000354228.3
ENSG00000272104	ENST00000606589.1	c.*106G>T		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000476225.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000268 AC: 2 AN: 747588 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 386026

African (AFR) AF: 0.00 AC: 0 AN: 17502

American (AMR) AF: 0.00 AC: 0 AN: 36760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14150

East Asian (EAS) AF: 0.00 AC: 0 AN: 15552

South Asian (SAS) AF: 0.00 AC: 0 AN: 73750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3606

European-Non Finnish (NFE) AF: 0.00000381 AC: 2 AN: 524452

Other (OTH) AF: 0.00 AC: 0 AN: 29012

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.0084	.;T;.;.;.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;.;.;.;L
PhyloP100		2.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.36	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.10	T;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T
Polyphen		0.0050, 0.0010	.;.;.;.;B;B
Vest4		0.34
MutPred		0.38		Loss of helix (P = 0.0626);.;.;.;.;Loss of helix (P = 0.0626);
MVP		0.18
MPC		0.58
ClinPred		0.23	T
GERP RS		3.3
Varity_R		0.070
gMVP		0.59
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs753131879; hg19: chr3-50405323;