Genetic Variant CACNA2D3:p.Leu65Phe (chr3-54123583-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018398.3(CACNA2D3):c.193C>T(p.Leu65Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CACNA2D3
NM_018398.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.75

Variant links:

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 links:

ENSG00000286353 (HGNC:):

ENSG00000286353 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D3	NM_018398.3 link	c.193C>T	p.Leu65Phe	missense_variant	Exon 2 of 38	ENST00000474759.6	NP_060868.2	Q8IZS8-1
LOC124909381	XR_007095914.1 link	n.-141G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6 link	c.193C>T	p.Leu65Phe	missense_variant	Exon 2 of 38	1	NM_018398.3	ENSP00000419101.1		Q8IZS8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249300

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461352

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726996

show subpopulations

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:

0.0000198

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

.;D;.

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.023

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.67

MutPred

0.29

Gain of methylation at K68 (P = 0.0694);Gain of methylation at K68 (P = 0.0694);Gain of methylation at K68 (P = 0.0694);

MVP

0.14

MPC

0.68

ClinPred

0.98

GERP RS

5.9

Varity_R

0.20

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over