3-54885553-C-G

Position:

• chr3-54885553-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018398.3(CACNA2D3):​c.2023C>G​(p.Leu675Val) 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. 13/21 in silico tools predict a benign 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: 2.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32479316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D3	NM_018398.3	c.2023C>G	p.Leu675Val	missense_variant	23/38	ENST00000474759.6	NP_060868.2
CACNA2D3-AS1	NR_046666.1	n.534-6609G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.2023C>G	p.Leu675Val	missense_variant	23/38	1	NM_018398.3	ENSP00000419101	P1
CACNA2D3-AS1	ENST00000471265.1	n.534-6609G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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.2023C>G (p.L675V) alteration is located in exon 23 (coding exon 23) of the CACNA2D3 gene. This alteration results from a C to G substitution at nucleotide position 2023, causing the leucine (L) at amino acid position 675 to be replaced by a valine (V). 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	Benign	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T;T;T;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;.;D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L;.
MutationTaster	Benign	0.59	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.49	T;T;T;T
Sift4G	Benign	0.074	T;T;T;T
Polyphen		0.13	B;B;B;.
Vest4		0.49
MutPred		0.34		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;
MVP		0.27
MPC		0.29
ClinPred		0.62	D
GERP RS		5.7
Varity_R		0.21
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs1699904062; hg19: chr3-54919580;