12-1860203-G-C

Variant names:

• chr12-1860203-G-C
• rs200098356
• NM_172364.5:c.1882C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_172364.5(CACNA2D4):​c.1882C>G​(p.Arg628Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

Genes affected

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.1882C>G	p.Arg628Gly	missense_variant	Exon 19 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.1882C>G	p.Arg628Gly	missense_variant	Exon 19 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.1882C>G	p.Arg628Gly	missense_variant	Exon 19 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.1807C>G	p.Arg603Gly	missense_variant	Exon 18 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.1690C>G	p.Arg564Gly	missense_variant	Exon 19 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.1690C>G	p.Arg564Gly	missense_variant	Exon 19 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*128C>G		non_coding_transcript_exon_variant	Exon 19 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*128C>G		3_prime_UTR_variant	Exon 19 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 34

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-6.0	D;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.97
MutPred		0.49		Loss of sheet (P = 0.0126);.;.;Loss of sheet (P = 0.0126);.;.;
MVP		0.31
MPC		0.70
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.87
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200098356; hg19: chr12-1969369;