rs141327265

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2BP4_StrongBP6_Very_StrongBP7BS1

The NM_006030.4(CACNA2D2):ā€‹c.669T>Cā€‹(p.Asn223=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,584,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00030 ( 0 hom., cov: 32)
Exomes š‘“: 0.00023 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.260
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
Variant 3-50381110-A-G is Benign according to our data. Variant chr3-50381110-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 416547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.26 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000297 (45/151450) while in subpopulation AMR AF= 0.00059 (9/15260). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA2D2NM_006030.4 linkuse as main transcriptc.669T>C p.Asn223= synonymous_variant 7/38 ENST00000424201.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA2D2ENST00000424201.7 linkuse as main transcriptc.669T>C p.Asn223= synonymous_variant 7/381 NM_006030.4 P4Q9NY47-2

Frequencies

GnomAD3 genomes
AF:
0.000291
AC:
44
AN:
151332
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000243
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000591
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000280
Gnomad OTH
AF:
0.00241
GnomAD3 exomes
AF:
0.000458
AC:
115
AN:
251146
Hom.:
0
AF XY:
0.000472
AC XY:
64
AN XY:
135726
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000868
Gnomad ASJ exome
AF:
0.00348
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000352
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.000232
AC:
332
AN:
1432738
Hom.:
0
Cov.:
33
AF XY:
0.000223
AC XY:
159
AN XY:
712922
show subpopulations
Gnomad4 AFR exome
AF:
0.000335
Gnomad4 AMR exome
AF:
0.000843
Gnomad4 ASJ exome
AF:
0.00338
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000698
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000116
Gnomad4 OTH exome
AF:
0.000632
GnomAD4 genome
AF:
0.000297
AC:
45
AN:
151450
Hom.:
0
Cov.:
32
AF XY:
0.000338
AC XY:
25
AN XY:
74048
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000590
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000280
Gnomad4 OTH
AF:
0.00238
Alfa
AF:
0.000491
Hom.:
0
Bravo
AF:
0.000291
EpiCase
AF:
0.000818
EpiControl
AF:
0.000712

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2023CACNA2D2: BP4, BP7 -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 11, 2020- -
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
CADD
Benign
3.9
DANN
Benign
0.65

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141327265; hg19: chr3-50418541; API