rs875989812

Positions:

• chr10-18150882-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP3_Moderate

The NM_201596.3(CACNB2):​c.121-1G>T variant causes a splice acceptor change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (0 hom., cov: 0)
  • Exomes 𝑓: 0.035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNB2 NM_201596.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.046394352 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.353

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.121-1G>T		splice_acceptor_variant		ENST00000324631.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.121-1G>T		splice_acceptor_variant		1	NM_201596.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 180 AN: 24742 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00493

Gnomad AMI AF: 0.00538

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.00256

Gnomad EAS AF: 0.00804

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.0263

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00602

GnomAD3 exomes AF: 0.000619 AC: 44 AN: 71112 Hom.: 0 AF XY: 0.000517 AC XY: 20 AN XY: 38656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.000970

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.000500

Gnomad OTH exome AF: 0.000734

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0353 AC: 10107 AN: 286308 Hom.: 0 Cov.: 8 AF XY: 0.0320 AC XY: 4841 AN XY: 151194

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.00835

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.00660

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.0458

Gnomad4 OTH exome AF: 0.0245

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00735 AC: 182 AN: 24770 Hom.: 0 Cov.: 0 AF XY: 0.00774 AC XY: 90 AN XY: 11630

Gnomad4 AFR AF: 0.00507

Gnomad4 AMR AF: 0.00944

Gnomad4 ASJ AF: 0.00256

Gnomad4 EAS AF: 0.00804

Gnomad4 SAS AF: 0.00627

Gnomad4 FIN AF: 0.0178

Gnomad4 NFE AF: 0.00783

Gnomad4 OTH AF: 0.00599

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 14
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs875989812; hg19: chr10-18439811;