9-137878081-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000718.4(CACNA1B):​c.148G>T​(p.Ala50Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000066 in 151,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.65
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4144146).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1BNM_000718.4 linkc.148G>T p.Ala50Ser missense_variant Exon 1 of 47 ENST00000371372.6 NP_000709.1 Q00975-1
CACNA1BNM_001243812.2 linkc.148G>T p.Ala50Ser missense_variant Exon 1 of 47 NP_001230741.1 Q00975-2
LOC100133077NR_121583.1 linkn.2692-2401C>A intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1BENST00000371372.6 linkc.148G>T p.Ala50Ser missense_variant Exon 1 of 47 5 NM_000718.4 ENSP00000360423.1 Q00975-1
CACNA1BENST00000371357.5 linkc.148G>T p.Ala50Ser missense_variant Exon 1 of 46 5 ENSP00000360408.1 B1AQK7
CACNA1BENST00000371363.5 linkc.148G>T p.Ala50Ser missense_variant Exon 1 of 46 5 ENSP00000360414.1 B1AQK6
CACNA1BENST00000277551.6 linkc.148G>T p.Ala50Ser missense_variant Exon 1 of 47 5 ENSP00000277551.2 Q00975-2

Frequencies

GnomAD3 genomes
AF:
0.00000660
AC:
1
AN:
151514
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000130
AC:
3
AN:
231300
Hom.:
0
AF XY:
0.00000794
AC XY:
1
AN XY:
125898
show subpopulations
Gnomad AFR exome
AF:
0.000223
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
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:
1190304
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
579170
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
AF:
0.00000660
AC:
1
AN:
151514
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
73988
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000249
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.148G>T (p.A50S) alteration is located in exon 1 (coding exon 1) of the CACNA1B gene. This alteration results from a G to T substitution at nucleotide position 148, causing the alanine (A) at amino acid position 50 to be replaced by a serine (S). 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
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
.;.;T;T;.;T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Benign
0.41
T;T;T;T;T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
M;.;M;.;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-2.2
N;.;N;N;N;N
REVEL
Pathogenic
0.78
Sift
Uncertain
0.0030
D;.;D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D;D;D
Polyphen
1.0
.;.;.;D;.;.
Vest4
0.43
MutPred
0.33
Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);
MVP
0.92
MPC
0.69
ClinPred
0.92
D
GERP RS
3.5
Varity_R
0.62
gMVP
0.38

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: rs750256540; hg19: chr9-140772533; COSMIC: COSV99496387; COSMIC: COSV99496387; API