rs966606951

Variant names:

• chr3-54122748-G-A
• rs966606951
• NM_018398.3:c.35G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-54122748-G-A
• chr3-54122748-G-C
• chr3-54122748-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018398.3(CACNA2D3):​c.35G>A​(p.Arg12Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000312 in 1,216,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 29)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12830162).

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.35G>A	p.Arg12Gln	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.35G>A	p.Arg12Gln	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000958523.1		c.35G>A	p.Arg12Gln	missense	Exon 1 of 37	ENSP00000628582.1
	CACNA2D3	ENST00000958525.1		c.35G>A	p.Arg12Gln	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 150724 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 22 AN: 1066146 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 9 AN XY: 503368

African (AFR) AF: 0.000449 AC: 10 AN: 22260

American (AMR) AF: 0.00 AC: 0 AN: 7814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13512

East Asian (EAS) AF: 0.00 AC: 0 AN: 25204

South Asian (SAS) AF: 0.00 AC: 0 AN: 19338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2824

European-Non Finnish (NFE) AF: 0.0000132 AC: 12 AN: 908866

Other (OTH) AF: 0.00 AC: 0 AN: 42348

GnomAD4 genome AF: 0.000106 AC: 16 AN: 150834 Hom.: 1 Cov.: 29 AF XY: 0.000122 AC XY: 9 AN XY: 73700

African (AFR) AF: 0.000315 AC: 13 AN: 41226

American (AMR) AF: 0.000132 AC: 2 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67580

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions as Germline

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	0.30
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.24	N
REVEL	Benign	0.026
Sift	Benign	0.42	T
Sift4G	Benign	0.37	T
Polyphen		0.066	B
Vest4		0.21
MutPred		0.38		Loss of MoRF binding (P = 0.0084)
MVP		0.093
MPC		0.30
ClinPred		0.60	D
GERP RS		4.2
PromoterAI		0.034	Neutral
Varity_R		0.15
gMVP		0.28
Mutation Taster		=89/11	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: rs966606951; hg19: chr3-54156775;