rs139719558

Variant summary

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

The NM_000718.4(CACNA1B):​c.228C>A​(p.Phe76Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 missense

Scores

6
6
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.04
Variant links:
Genes affected
CACNA1B (HGNC:1389): (calcium voltage-gated channel subunit alpha1 B) The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 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, 0.755

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1BNM_000718.4 linkc.228C>A p.Phe76Leu missense_variant Exon 1 of 47 ENST00000371372.6 NP_000709.1 Q00975-1
CACNA1BNM_001243812.2 linkc.228C>A p.Phe76Leu missense_variant Exon 1 of 47 NP_001230741.1 Q00975-2
LOC100133077NR_121583.1 linkn.2692-2481G>T intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1BENST00000371372.6 linkc.228C>A p.Phe76Leu missense_variant Exon 1 of 47 5 NM_000718.4 ENSP00000360423.1 Q00975-1
CACNA1BENST00000371357.5 linkc.228C>A p.Phe76Leu missense_variant Exon 1 of 46 5 ENSP00000360408.1 B1AQK7
CACNA1BENST00000371363.5 linkc.228C>A p.Phe76Leu missense_variant Exon 1 of 46 5 ENSP00000360414.1 B1AQK6
CACNA1BENST00000277551.6 linkc.228C>A p.Phe76Leu missense_variant Exon 1 of 47 5 ENSP00000277551.2 Q00975-2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000814
AC:
2
AN:
245602
Hom.:
0
AF XY:
0.00000748
AC XY:
1
AN XY:
133610
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000665
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1152904
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
555594
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.00000826
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.050
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
.;.;D;T;.;T
Eigen
Benign
0.13
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D;D
MetaSVM
Benign
-0.62
T
MutationAssessor
Uncertain
2.6
M;.;M;.;.;.
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-4.4
D;.;D;D;D;D
REVEL
Uncertain
0.34
Sift
Benign
0.13
T;.;D;D;D;D
Sift4G
Benign
0.15
T;T;T;T;T;T
Polyphen
0.70
.;.;.;P;.;.
Vest4
0.62
MutPred
0.74
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.64
MPC
0.78
ClinPred
0.92
D
GERP RS
3.5
Varity_R
0.86
gMVP
0.77

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs139719558; hg19: chr9-140772613; API