chr12-1860203-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_172364.5(CACNA2D4):ā€‹c.1882C>Gā€‹(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: š‘“ 0.0000066 ( 0 hom., cov: 34)

Consequence

CACNA2D4
NM_172364.5 missense

Scores

7
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45
Variant links:
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]

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ACMG classification

Classification made for transcript

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
CACNA2D4NM_172364.5 linkc.1882C>G p.Arg628Gly missense_variant Exon 19 of 38 ENST00000382722.10 NP_758952.4 Q7Z3S7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA2D4ENST00000382722.10 linkc.1882C>G p.Arg628Gly missense_variant Exon 19 of 38 1 NM_172364.5 ENSP00000372169.4 Q7Z3S7-1
CACNA2D4ENST00000586184.5 linkc.1882C>G p.Arg628Gly missense_variant Exon 19 of 37 5 ENSP00000465060.1 Q7Z3S7-5
CACNA2D4ENST00000587995.5 linkc.1807C>G p.Arg603Gly missense_variant Exon 18 of 37 5 ENSP00000465372.1 K7EJY1
CACNA2D4ENST00000585708.5 linkc.1690C>G p.Arg564Gly missense_variant Exon 19 of 37 5 ENSP00000467697.1 Q7Z3S7-6
CACNA2D4ENST00000588077.5 linkc.1690C>G p.Arg564Gly missense_variant Exon 19 of 38 5 ENSP00000468530.1 Q7Z3S7-4
CACNA2D4ENST00000444595.6 linkn.*128C>G non_coding_transcript_exon_variant Exon 19 of 37 1 ENSP00000403371.2 E7EUE0
CACNA2D4ENST00000444595.6 linkn.*128C>G 3_prime_UTR_variant Exon 19 of 37 1 ENSP00000403371.2 E7EUE0

Frequencies

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200098356; hg19: chr12-1969369; API