chr3-50366345-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006030.4(CACNA2D2):c.2638-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 splice_region, intron

Scores

Splicing: ADA: 0.0006402

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.12

Publications

0 publications found

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 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

CACNA2D2 links:

ENSG00000272104 (HGNC:):

ENSG00000272104 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 3-50366345-G-C is Benign according to our data. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-50366345-G-C is described in CliVar as Likely_benign. Clinvar id is 461315.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.2638-7C>G		splice_region_variant, intron_variant	Intron 30 of 37	ENST00000424201.7	NP_006021.2	Q9NY47-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D2	ENST00000424201.7 link	c.2638-7C>G	splice_region_variant, intron_variant	Intron 30 of 37	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.2662-7C>G	splice_region_variant, intron_variant	Intron 31 of 38	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.2638-7C>G	splice_region_variant, intron_variant	Intron 30 of 37	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.2431-7C>G	splice_region_variant, intron_variant	Intron 30 of 37	1		ENSP00000354228.3	Q9NY47-4
ENSG00000272104	ENST00000606589.1 link	c.*9+14G>C	intron_variant	Intron 3 of 3	3		ENSP00000476225.1	U3KQU4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111790

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.9

(source)

DANN

Benign

0.64

PhyloP100

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00064

dbscSNV1_RF

Benign

0.066

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over