3-54891399-C-T

Position:

• chr3-54891399-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018398.3(CACNA2D3):​c.2195C>T​(p.Thr732Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00967 in 1,613,880 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (73 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014728785).
• BP6: Variant 3-54891399-C-T is Benign according to our data. Variant chr3-54891399-C-T is described in ClinVar as [Benign]. Clinvar id is 773444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D3	NM_018398.3	c.2195C>T	p.Thr732Met	missense_variant	25/38	ENST00000474759.6	NP_060868.2
CACNA2D3-AS1	NR_046666.1	n.533+3214G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.2195C>T	p.Thr732Met	missense_variant	25/38	1	NM_018398.3	ENSP00000419101	P1
CACNA2D3	ENST00000490478.5	c.1913C>T	p.Thr638Met	missense_variant	24/37	1		ENSP00000417279
CACNA2D3	ENST00000471363.5	c.*273C>T		3_prime_UTR_variant, NMD_transcript_variant	22/35	1		ENSP00000418228
CACNA2D3-AS1	ENST00000471265.1	n.533+3214G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1150 AN: 152134 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00768 AC: 1914 AN: 249180 Hom.: 14 AF XY: 0.00752 AC XY: 1016 AN XY: 135168

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00810

GnomAD4 exome AF: 0.00989 AC: 14460 AN: 1461628 Hom.: 73 Cov.: 31 AF XY: 0.00972 AC XY: 7069 AN XY: 727106

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00740

GnomAD4 genome AF: 0.00757 AC: 1152 AN: 152252 Hom.: 9 Cov.: 32 AF XY: 0.00779 AC XY: 580 AN XY: 74436

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00842 Hom.: 15

Bravo AF: 0.00574

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00213 AC: 8

ESP6500EA AF: 0.0111 AC: 91

ExAC AF: 0.00761 AC: 919

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00759

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2018

- -

CACNA2D3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	.;D;.;D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.94
MVP		0.19
MPC		0.91
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.86

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: rs112362995; hg19: chr3-54925426;