chr3-54122727-G-T

Variant names:

• chr3-54122727-G-T
• rs1010591572
• NM_018398.3:c.14G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018398.3(CACNA2D3):​c.14G>T​(p.Gly5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,204,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• Publications: 1 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]

ENSG00000286353 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13803521).

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.14G>T	p.Gly5Val	missense	Exon 1 of 38	NP_060868.2	Q8IZS8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.14G>T	p.Gly5Val	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000958523.1		c.14G>T	p.Gly5Val	missense	Exon 1 of 37	ENSP00000628582.1
	CACNA2D3	ENST00000958525.1		c.14G>T	p.Gly5Val	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 150292 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000741

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000484 AC: 51 AN: 1054516 Hom.: 0 Cov.: 30 AF XY: 0.0000462 AC XY: 23 AN XY: 497658

African (AFR) AF: 0.00 AC: 0 AN: 21854

American (AMR) AF: 0.00 AC: 0 AN: 7456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13074

East Asian (EAS) AF: 0.0000826 AC: 2 AN: 24226

South Asian (SAS) AF: 0.00 AC: 0 AN: 19278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.0000521 AC: 47 AN: 902552

Other (OTH) AF: 0.0000481 AC: 2 AN: 41576

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 150292 Hom.: 0 Cov.: 29 AF XY: 0.0000273 AC XY: 2 AN XY: 73380

African (AFR) AF: 0.00 AC: 0 AN: 41044

American (AMR) AF: 0.00 AC: 0 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000741 AC: 5 AN: 67462

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

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	0.098
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.080	N
REVEL	Benign	0.029
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		0.010	B
Vest4		0.12
MutPred		0.20		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.043
MPC		0.33
ClinPred		0.58	D
GERP RS		3.3
PromoterAI		-0.033	Neutral
Varity_R		0.20
gMVP		0.25
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1010591572; hg19: chr3-54156754;