10-18150881-A-T

Position:

• chr10-18150881-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_201596.3(CACNB2):​c.121-2A>T variant causes a splice acceptor, intron 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 0.040 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNB2 NM_201596.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.59

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]

CACNB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.121-2A>T		splice_acceptor_variant, intron_variant		ENST00000324631.13	NP_963890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.121-2A>T		splice_acceptor_variant, intron_variant		1	NM_201596.3	ENSP00000320025.8

Frequencies

GnomAD3 genomes AF: 0.00 AC: 584 AN: 14454 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.0345

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.0278

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0275

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00505 AC: 1409 AN: 278968 Hom.: 0 Cov.: 6 AF XY: 0.00495 AC XY: 722 AN XY: 145936

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00158

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.00560

Gnomad4 OTH exome AF: 0.00367

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0403 AC: 583 AN: 14458 Hom.: 0 Cov.: 0 AF XY: 0.0360 AC XY: 261 AN XY: 7256

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.0348

Gnomad4 ASJ AF: 0.0278

Gnomad4 EAS AF: 0.0263

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.0304

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0273

ExAC AF: 0.0000336 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 15
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750396182; hg19: chr10-18439810;