chr3-54896746-A-G

Variant names:

• chr3-54896746-A-G
• rs17253119
• NM_018398.3:c.2247-3A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_018398.3(CACNA2D3):​c.2247-3A>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 0.111 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, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018398.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	NM_018398.3	MANE Select	c.2247-3A>G		splice_region intron	N/A	NP_060868.2
	CACNA2D3-AS1	NR_046666.1		n.310T>C		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.2247-3A>G		splice_region intron	N/A	ENSP00000419101.1
	CACNA2D3	ENST00000490478.5	TSL:1	c.1965-3A>G		splice_region intron	N/A	ENSP00000417279.1
	CACNA2D3	ENST00000471363.5	TSL:1	n.*325-3A>G		splice_region intron	N/A	ENSP00000418228.1

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

GnomAD2 exomes AF: 0.0907 AC: 22609 AN: 249272 AF XY: 0.0899

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 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

African (AFR) AF: 0.151 AC: 5045 AN: 33472

American (AMR) AF: 0.0473 AC: 2117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 848 AN: 26136

East Asian (EAS) AF: 0.0132 AC: 524 AN: 39700

South Asian (SAS) AF: 0.0615 AC: 5309 AN: 86258

European-Finnish (FIN) AF: 0.131 AC: 6983 AN: 53402

Middle Eastern (MID) AF: 0.0785 AC: 453 AN: 5768

European-Non Finnish (NFE) AF: 0.121 AC: 134091 AN: 1111696

Other (OTH) AF: 0.105 AC: 6338 AN: 60368

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

African (AFR) AF: 0.153 AC: 6350 AN: 41508

American (AMR) AF: 0.0748 AC: 1144 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5164

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4820

European-Finnish (FIN) AF: 0.132 AC: 1397 AN: 10576

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7971 AN: 67986

Other (OTH) AF: 0.0992 AC: 210 AN: 2116

Alfa AF: 0.107 Hom.: 831

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.7
DANN	Benign	0.63
PhyloP100		2.0
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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