chr3-54899841-G-A

Variant names:

• chr3-54899841-G-A
• rs1009964575
• NM_018398.3:c.2422G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018398.3(CACNA2D3):​c.2422G>A​(p.Asp808Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D808G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.80
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	NM_018398.3	MANE Select	c.2422G>A	p.Asp808Asn	missense	Exon 27 of 38	NP_060868.2	Q8IZS8-1
	CACNA2D3-AS1	NR_046666.1		n.97+1318C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.2422G>A	p.Asp808Asn	missense	Exon 27 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000490478.5	TSL:1	c.2140G>A	p.Asp714Asn	missense	Exon 26 of 37	ENSP00000417279.1	Q8IZS8-2
	CACNA2D3	ENST00000471363.5	TSL:1	n.*500G>A		non_coding_transcript_exon	Exon 24 of 35	ENSP00000418228.1	Q8IZS8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454570 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722558

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 43896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 84322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108544

Other (OTH) AF: 0.00 AC: 0 AN: 60134

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.36	T
Sift4G	Benign	0.087	T
Polyphen		0.29	B
Vest4		0.78
MutPred		0.28		Loss of ubiquitination at K811 (P = 0.1087)
MVP		0.55
MPC		0.82
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.55
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1009964575; hg19: chr3-54933868;