rs41305892

Positions:

• chr3-50375821-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006030.4(CACNA2D2):​c.1833G>A​(p.Lys611Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,613,048 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (26 hom.)
• Consequence: CACNA2D2 NM_006030.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.957

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-50375821-C-T is Benign according to our data. Variant chr3-50375821-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.957 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00307 (467/152300) while in subpopulation NFE AF= 0.00448 (305/68012). AF 95% confidence interval is 0.00407. There are 1 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D2	NM_006030.4	c.1833G>A	p.Lys611Lys	synonymous_variant	20/38	ENST00000424201.7	NP_006021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D2	ENST00000424201.7	c.1833G>A	p.Lys611Lys	synonymous_variant	20/38	1	NM_006030.4	ENSP00000390329.2
CACNA2D2	ENST00000423994.6	c.1833G>A	p.Lys611Lys	synonymous_variant	20/39	5		ENSP00000407393.2
CACNA2D2	ENST00000266039.7	c.1833G>A	p.Lys611Lys	synonymous_variant	20/38	1		ENSP00000266039.3
CACNA2D2	ENST00000360963.7	c.1626G>A	p.Lys542Lys	synonymous_variant	20/38	1		ENSP00000354228.3

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 468 AN: 152182 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00448

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00371 AC: 931 AN: 251070 Hom.: 5 AF XY: 0.00379 AC XY: 515 AN XY: 135840

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00271

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00345 AC: 5041 AN: 1460748 Hom.: 26 Cov.: 35 AF XY: 0.00357 AC XY: 2594 AN XY: 726682

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.00160

Gnomad4 NFE exome AF: 0.00348

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.00295 AC XY: 220 AN XY: 74466

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00448

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00416 Hom.: 3

Bravo AF: 0.00337

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00723

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CACNA2D2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	11
DANN	Benign	0.81

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

Other links and lift over

dbSNP: rs41305892; hg19: chr3-50413252;