9-137878085-AGC-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000718.4(CACNA1B):​c.160_161delCG​(p.Arg54AspfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000025 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90
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 Pathogenic. Variant got 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1BNM_000718.4 linkc.160_161delCG p.Arg54AspfsTer66 frameshift_variant Exon 1 of 47 ENST00000371372.6 NP_000709.1 Q00975-1
CACNA1BNM_001243812.2 linkc.160_161delCG p.Arg54AspfsTer66 frameshift_variant Exon 1 of 47 NP_001230741.1 Q00975-2
LOC100133077NR_121583.1 linkn.2692-2407_2692-2406delGC intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1BENST00000371372.6 linkc.160_161delCG p.Arg54AspfsTer66 frameshift_variant Exon 1 of 47 5 NM_000718.4 ENSP00000360423.1 Q00975-1
CACNA1BENST00000371357.5 linkc.160_161delCG p.Arg54AspfsTer66 frameshift_variant Exon 1 of 46 5 ENSP00000360408.1 B1AQK7
CACNA1BENST00000371363.5 linkc.160_161delCG p.Arg54AspfsTer66 frameshift_variant Exon 1 of 46 5 ENSP00000360414.1 B1AQK6
CACNA1BENST00000277551.6 linkc.160_161delCG p.Arg54AspfsTer66 frameshift_variant Exon 1 of 47 5 ENSP00000277551.2 Q00975-2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000252
AC:
3
AN:
1190878
Hom.:
0
AF XY:
0.00000345
AC XY:
2
AN XY:
579460
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000579
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:
0.00000206
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
May 09, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140772537; API