rs8181477

Variant names:

• chr10-18493951-A-C
• rs8181477
• NM_201596.3:c.334-4404A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_201596.3(CACNB2):​c.334-4404A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 151,980 control chromosomes in the GnomAD database, including 14,806 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (14806 hom., cov: 31)
• Consequence: CACNB2 NM_201596.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome 4

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.334-4404A>C		intron_variant	Intron 3 of 13	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.172-4404A>C		intron_variant	Intron 2 of 12	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.334-4404A>C		intron_variant	Intron 3 of 13	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.172-4404A>C		intron_variant	Intron 2 of 12	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66365 AN: 151862 Hom.: 14807 Cov.: 31

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.461

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.437 AC: 66390 AN: 151980 Hom.: 14806 Cov.: 31 AF XY: 0.439 AC XY: 32582 AN XY: 74264

African (AFR) AF: 0.392 AC: 16257 AN: 41470

American (AMR) AF: 0.418 AC: 6380 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1344 AN: 3470

East Asian (EAS) AF: 0.699 AC: 3606 AN: 5160

South Asian (SAS) AF: 0.482 AC: 2318 AN: 4808

European-Finnish (FIN) AF: 0.456 AC: 4812 AN: 10544

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30140 AN: 67948

Other (OTH) AF: 0.456 AC: 961 AN: 2108

Alfa AF: 0.439 Hom.: 50043

Bravo AF: 0.434

Asia WGS AF: 0.533 AC: 1853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.74
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8181477; hg19: chr10-18782880;