12-48823700-C-T

Variant summary

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

The NM_000725.4(CACNB3):​c.188C>T​(p.Ala63Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CACNB3
NM_000725.4 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
CACNB3 (HGNC:1403): (calcium voltage-gated channel auxiliary subunit beta 3) This gene encodes a regulatory beta subunit of the voltage-dependent calcium channel. Beta subunits are composed of five domains, which contribute to the regulation of surface expression and gating of calcium channels and may also play a role in the regulation of transcription factors and calcium transport. [provided by RefSeq, Oct 2011]

Genome browser will be placed here

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, 0.834

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNB3NM_000725.4 linkuse as main transcriptc.188C>T p.Ala63Val missense_variant 3/13 ENST00000301050.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNB3ENST00000301050.7 linkuse as main transcriptc.188C>T p.Ala63Val missense_variant 3/131 NM_000725.4 P1P54284-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251414
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461864
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74302
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
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2023The c.188C>T (p.A63V) alteration is located in exon 3 (coding exon 3) of the CACNB3 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the alanine (A) at amino acid position 63 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.73
.;.;.;D;.;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Uncertain
2.8
.;.;.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.5
D;D;D;D;D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.029
D;D;D;D;D;D
Sift4G
Uncertain
0.045
D;D;D;D;D;D
Polyphen
0.99
.;.;.;D;.;.
Vest4
0.89
MutPred
0.54
.;.;Gain of catalytic residue at N67 (P = 0.001);Gain of catalytic residue at N67 (P = 0.001);Gain of catalytic residue at N67 (P = 0.001);.;
MVP
0.89
MPC
1.1
ClinPred
0.92
D
GERP RS
4.9
Varity_R
0.49
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs774926593; hg19: chr12-49217483; API