chr3-54122790-C-T

Variant names:

• chr3-54122790-C-T
• rs1191834640
• NM_018398.3:c.77C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018398.3(CACNA2D3):​c.77C>T​(p.Ala26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000974 in 1,231,618 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 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10470444).

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.77C>T	p.Ala26Val	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.77C>T	p.Ala26Val	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000958523.1		c.77C>T	p.Ala26Val	missense	Exon 1 of 37	ENSP00000628582.1
	CACNA2D3	ENST00000958525.1		c.77C>T	p.Ala26Val	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151772 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000833 AC: 9 AN: 1079846 Hom.: 0 Cov.: 31 AF XY: 0.00000784 AC XY: 4 AN XY: 510006

African (AFR) AF: 0.00 AC: 0 AN: 22582

American (AMR) AF: 0.00 AC: 0 AN: 8118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13982

East Asian (EAS) AF: 0.00 AC: 0 AN: 25998

South Asian (SAS) AF: 0.00 AC: 0 AN: 19440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2882

European-Non Finnish (NFE) AF: 0.00000984 AC: 9 AN: 914960

Other (OTH) AF: 0.00 AC: 0 AN: 43046

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151772 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74120

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.070
Sift	Benign	0.32	T
Sift4G	Benign	0.71	T
Polyphen		0.012	B
Vest4		0.19
MutPred		0.36		Loss of loop (P = 0.0112)
MVP		0.043
MPC		0.26
ClinPred		0.74	D
GERP RS		4.6
PromoterAI		0.0068	Neutral
Varity_R		0.17
gMVP		0.24
Mutation Taster		=77/23	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: rs1191834640; hg19: chr3-54156817; COSMIC: COSV107297118; COSMIC: COSV107297118;