chr3-54122760-C-T

Variant names:

• chr3-54122760-C-T
• NM_018398.3:c.47C>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.47C>T​(p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.418
• 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]

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=0.12756792).

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.47C>T	p.Ala16Val	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.47C>T	p.Ala16Val	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000958523.1		c.47C>T	p.Ala16Val	missense	Exon 1 of 37	ENSP00000628582.1
	CACNA2D3	ENST00000958525.1		c.47C>T	p.Ala16Val	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1072962 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 506694

African (AFR) AF: 0.00 AC: 0 AN: 22472

American (AMR) AF: 0.00 AC: 0 AN: 8006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13768

East Asian (EAS) AF: 0.00 AC: 0 AN: 25710

South Asian (SAS) AF: 0.00 AC: 0 AN: 19410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2862

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 912476

Other (OTH) AF: 0.00 AC: 0 AN: 42742

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	CACNA2D3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.42
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.065
Sift	Benign	0.22	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.38		Gain of loop (P = 0.0079)
MVP		0.068
MPC		0.26
ClinPred		0.33	T
GERP RS		3.1
PromoterAI		-0.0050	Neutral
Varity_R		0.063
gMVP		0.21
Mutation Taster		=86/14	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

hg19: chr3-54156787;