3-54562940-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018398.3(CACNA2D3):c.676+9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,611,664 control chromosomes in the GnomAD database, including 4,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.093 (1555 hom., cov: 32)
  • Exomes 𝑓: 0.025 (2534 hom.)
• Consequence: CACNA2D3 NM_018398.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31

Genes affected

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-54562940-A-C is Benign according to our data. Variant chr3-54562940-A-C is described in ClinVar as [Benign]. Clinvar id is 1269269.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D3	NM_018398.3	c.676+9A>C		intron_variant		ENST00000474759.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.676+9A>C		intron_variant		1	NM_018398.3	P1

Frequencies

GnomAD3 genomes AF: 0.0928 AC: 14117 AN: 152110 Hom.: 1555 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00878

Gnomad OTH AF: 0.0705

GnomAD3 exomes AF: 0.0563 AC: 13989 AN: 248376 Hom.: 1184 AF XY: 0.0477 AC XY: 6431 AN XY: 134752

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.00697

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.0318

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00762

Gnomad OTH exome AF: 0.0306

GnomAD4 exome AF: 0.0250 AC: 36505 AN: 1459436 Hom.: 2534 Cov.: 30 AF XY: 0.0240 AC XY: 17402 AN XY: 726044

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.00621

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.0322

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.00793

Gnomad4 OTH exome AF: 0.0389

GnomAD4 genome AF: 0.0928 AC: 14124 AN: 152228 Hom.: 1555 Cov.: 32 AF XY: 0.0927 AC XY: 6904 AN XY: 74438

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.0812

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.0361

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.00878

Gnomad4 OTH AF: 0.0712

Alfa AF: 0.0724 Hom.: 400

Bravo AF: 0.108

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.2
Dann	Benign	0.68

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: rs41277449; hg19: chr3-54596967; COSMIC: COSV55524063; COSMIC: COSV55524063;