3-54122753-G-T

Variant names:

• chr3-54122753-G-T
• rs1468343451
• NM_018398.3:c.40G>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.40G>T​(p.Ala14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000934 in 1,070,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271
• 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=0.105673134).

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.40G>T	p.Ala14Ser	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.40G>T	p.Ala14Ser	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000958523.1		c.40G>T	p.Ala14Ser	missense	Exon 1 of 37	ENSP00000628582.1
	CACNA2D3	ENST00000958525.1		c.40G>T	p.Ala14Ser	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 9.34e-7 AC: 1 AN: 1070680 Hom.: 0 Cov.: 30 AF XY: 0.00000198 AC XY: 1 AN XY: 505604

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22388

American (AMR) AF: 0.00 AC: 0 AN: 7956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13706

East Asian (EAS) AF: 0.00 AC: 0 AN: 25522

South Asian (SAS) AF: 0.0000516 AC: 1 AN: 19388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 911526

Other (OTH) AF: 0.00 AC: 0 AN: 42632

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.27
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.40	N
REVEL	Benign	0.028
Sift	Benign	0.82	T
Sift4G	Benign	0.74	T
Polyphen		0.0050	B
Vest4		0.21
MutPred		0.33		Gain of loop (P = 0.0045)
MVP		0.14
MPC		0.24
ClinPred		0.11	T
GERP RS		0.63
PromoterAI		-0.14	Neutral
Varity_R		0.070
gMVP		0.31
Mutation Taster		=96/4	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: rs1468343451; hg19: chr3-54156780;