3-54887985-C-T

Position:

• chr3-54887985-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018398.3(CACNA2D3):​c.2083C>T​(p.Leu695Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D3	NM_018398.3	c.2083C>T	p.Leu695Phe	missense_variant	24/38	ENST00000474759.6
CACNA2D3-AS1	NR_046666.1	n.533+6628G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.2083C>T	p.Leu695Phe	missense_variant	24/38	1	NM_018398.3	P1
CACNA2D3-AS1	ENST00000471265.1	n.533+6628G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.2083C>T (p.L695F) alteration is located in exon 24 (coding exon 24) of the CACNA2D3 gene. This alteration results from a C to T substitution at nucleotide position 2083, causing the leucine (L) at amino acid position 695 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.84
MutPred		0.45		Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);.;
MVP		0.73
MPC		0.98
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.72

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: chr3-54922012;