chr3-54122723-C-T

Variant names:

• chr3-54122723-C-T
• rs953912496
• NM_018398.3:c.10C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018398.3(CACNA2D3):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,199,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.370
• Publications: 0 publications found

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]

ENSG00000286353 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06748229).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018398.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	NM_018398.3	MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 38	NP_060868.2	Q8IZS8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000958523.1		c.10C>T	p.Pro4Ser	missense	Exon 1 of 37	ENSP00000628582.1
	CACNA2D3	ENST00000958525.1		c.10C>T	p.Pro4Ser	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes AF: 0.0000932 AC: 14 AN: 150220 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 11 AN: 1049680 Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 5 AN XY: 495306

African (AFR) AF: 0.000507 AC: 11 AN: 21686

American (AMR) AF: 0.00 AC: 0 AN: 7298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12884

East Asian (EAS) AF: 0.00 AC: 0 AN: 23816

South Asian (SAS) AF: 0.00 AC: 0 AN: 19230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 899682

Other (OTH) AF: 0.00 AC: 0 AN: 41222

GnomAD4 genome AF: 0.0000932 AC: 14 AN: 150220 Hom.: 0 Cov.: 29 AF XY: 0.0000818 AC XY: 6 AN XY: 73340

African (AFR) AF: 0.000341 AC: 14 AN: 41070

American (AMR) AF: 0.00 AC: 0 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67442

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.37
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.031
Sift	Benign	0.50	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.096
MutPred		0.24		Gain of phosphorylation at P4 (P = 0.0084)
MVP		0.068
MPC		0.27
ClinPred		0.34	T
GERP RS		3.2
PromoterAI		-0.072	Neutral
Varity_R		0.063
gMVP		0.21
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs953912496; hg19: chr3-54156750;