10-18358575-A-G

Variant names:

• chr10-18358575-A-G
• rs12356676
• NM_201596.3:c.214-43349A>G

Variant summary

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

The NM_201596.3(CACNB2):​c.214-43349A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 141,010 control chromosomes in the GnomAD database, including 34,136 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 0.70 (34136 hom., cov: 23)
• Consequence: CACNB2 NM_201596.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 2 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=-1.12).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201596.3	MANE Select	c.214-43349A>G		intron	N/A	NP_963890.2
	CACNB2	NM_201590.3	MANE Plus Clinical	c.51+17598A>G		intron	N/A	NP_963884.2
	CACNB2	NM_201597.3		c.214-43349A>G		intron	N/A	NP_963891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.214-43349A>G		intron	N/A	ENSP00000320025.8
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.51+17598A>G		intron	N/A	ENSP00000366546.4
	CACNB2	ENST00000352115.10	TSL:1	c.214-43349A>G		intron	N/A	ENSP00000344474.6

Frequencies

GnomAD3 genomes AF: 0.698 AC: 98391 AN: 140922 Hom.: 34127 Cov.: 23

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.739

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.684

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

GnomAD4 genome AF: 0.698 AC: 98434 AN: 141010 Hom.: 34136 Cov.: 23 AF XY: 0.699 AC XY: 47573 AN XY: 68072

African (AFR) AF: 0.645 AC: 24120 AN: 37398

American (AMR) AF: 0.741 AC: 10436 AN: 14092

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1894 AN: 3316

East Asian (EAS) AF: 0.353 AC: 1459 AN: 4136

South Asian (SAS) AF: 0.737 AC: 3258 AN: 4422

European-Finnish (FIN) AF: 0.768 AC: 6884 AN: 8958

Middle Eastern (MID) AF: 0.729 AC: 188 AN: 258

European-Non Finnish (NFE) AF: 0.734 AC: 48188 AN: 65640

Other (OTH) AF: 0.680 AC: 1294 AN: 1902

Alfa AF: 0.688 Hom.: 4162

Bravo AF: 0.664

Asia WGS AF: 0.495 AC: 1643 AN: 3316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	2.7
DANN	Benign	0.62
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12356676; hg19: chr10-18647504;