3-50365164-A-G

Variant names:

• chr3-50365164-A-G
• rs587776948
• NM_006030.4:c.3119T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006030.4(CACNA2D2):​c.3119T>C​(p.Leu1040Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L1040L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D2 NM_006030.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.40
• Publications: 10 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-50365164-A-G is Pathogenic according to our data. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-50365164-A-G is described in CliVar as Pathogenic. Clinvar id is 40230.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.3119T>C	p.Leu1040Pro	missense_variant	Exon 36 of 38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.3119T>C	p.Leu1040Pro	missense_variant	Exon 36 of 38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.3143T>C	p.Leu1048Pro	missense_variant	Exon 37 of 39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.3119T>C	p.Leu1040Pro	missense_variant	Exon 36 of 38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.2912T>C	p.Leu971Pro	missense_variant	Exon 36 of 38	1		ENSP00000354228.3
ENSG00000272104	ENST00000606589.1	c.128-1133A>G		intron_variant	Intron 2 of 3	3		ENSP00000476225.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebellar atrophy with seizures and variable developmental delay Pathogenic:1

Feb 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;T;.;.;.;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;M
PhyloP100		8.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;D;D
Vest4		0.97
MutPred		0.87		.;.;.;.;.;Loss of stability (P = 0.0089);
MVP		0.73
MPC		1.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.85
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs587776948; hg19: chr3-50402595;