rs139046100

Variant names:

• chr3-50377486-C-G
• rs139046100
• NM_006030.4:c.1607G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-50377486-C-G
• chr3-50377486-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006030.4(CACNA2D2):​c.1607G>C​(p.Arg536Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R536K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.307
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38265127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.1607G>C	p.Arg536Thr	missense_variant	Exon 17 of 38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.1607G>C	p.Arg536Thr	missense_variant	Exon 17 of 38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.1607G>C	p.Arg536Thr	missense_variant	Exon 17 of 39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.1607G>C	p.Arg536Thr	missense_variant	Exon 17 of 38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1400G>C	p.Arg467Thr	missense_variant	Exon 17 of 38	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.11	.;T;.;.;.;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;L;.;L;L
PhyloP100		0.31
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D
REVEL	Benign	0.089
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		0.55, 0.61	.;.;.;.;P;P
Vest4		0.57
MutPred		0.54		Gain of ubiquitination at K535 (P = 0.0601);Gain of ubiquitination at K535 (P = 0.0601);Gain of ubiquitination at K535 (P = 0.0601);.;Gain of ubiquitination at K535 (P = 0.0601);Gain of ubiquitination at K535 (P = 0.0601);
MVP		0.13
MPC		0.99
ClinPred		0.96	D
GERP RS		2.4
Varity_R		0.23
gMVP		0.72
Mutation Taster		=50/50

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: rs139046100; hg19: chr3-50414917;