rs17253119

Positions:

• chr3-54896746-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_018398.3(CACNA2D3):​c.2247-3A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,613,662 control chromosomes in the GnomAD database, including 10,957 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1148 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9809 hom.)
• Consequence: CACNA2D3 NM_018398.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95

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]

CACNA2D3-AS1 (HGNC:40702): (CACNA2D3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D3	NM_018398.3	c.2247-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000474759.6
CACNA2D3-AS1	NR_046666.1	n.310T>C		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.2247-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018398.3	P1
CACNA2D3	ENST00000490478.5	c.1965-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
CACNA2D3-AS1	ENST00000471265.1	n.310T>C		non_coding_transcript_exon_variant	2/7	2
CACNA2D3	ENST00000471363.5	c.*325-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17544 AN: 152020 Hom.: 1146 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0527

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.0907 AC: 22609 AN: 249272 Hom.: 1252 AF XY: 0.0899 AC XY: 12162 AN XY: 135228

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.00851

Gnomad SAS exome AF: 0.0597

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.0961

GnomAD4 exome AF: 0.111 AC: 161708 AN: 1461524 Hom.: 9809 Cov.: 32 AF XY: 0.109 AC XY: 79040 AN XY: 727062

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.0473

Gnomad4 ASJ exome AF: 0.0324

Gnomad4 EAS exome AF: 0.0132

Gnomad4 SAS exome AF: 0.0615

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.115 AC: 17553 AN: 152138 Hom.: 1148 Cov.: 32 AF XY: 0.113 AC XY: 8398 AN XY: 74364

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0748

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0529

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.0992

Alfa AF: 0.108 Hom.: 632

Bravo AF: 0.111

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.7
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs17253119; hg19: chr3-54930773; COSMIC: COSV55515614;