3-54122760-C-T

Position:

• chr3-54122760-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 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

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12756792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D3	NM_018398.3	c.47C>T	p.Ala16Val	missense_variant	1/38	ENST00000474759.6	NP_060868.2
LOC124909381	XR_007095914.1	n.386+297G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.47C>T	p.Ala16Val	missense_variant	1/38	1	NM_018398.3	ENSP00000419101	P1
	ENST00000666932.1	n.1187+297G>A		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CACNA2D3-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The CACNA2D3 c.47C>T variant is predicted to result in the amino acid substitution p.Ala16Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

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;T;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;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.17
MutPred		0.38		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.068
MPC		0.26
ClinPred		0.33	T
GERP RS		3.1
Varity_R		0.063
gMVP		0.21

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-54156787;