10-18312999-T-C

Variant names:

• chr10-18312999-T-C
• rs2799573
• NM_201596.3:c.214-88925T>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.214-88925T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 152,124 control chromosomes in the GnomAD database, including 4,033 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 0.20 (4033 hom., cov: 31)
• Consequence: CACNB2 NM_201596.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 24 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 (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.214-88925T>C		intron_variant	Intron 2 of 13	ENST00000324631.13	NP_963890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.214-88925T>C		intron_variant	Intron 2 of 13	1	NM_201596.3	ENSP00000320025.8

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30594 AN: 152006 Hom.: 4028 Cov.: 31

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.201 AC: 30598 AN: 152124 Hom.: 4033 Cov.: 31 AF XY: 0.200 AC XY: 14836 AN XY: 74350

African (AFR) AF: 0.0530 AC: 2201 AN: 41532

American (AMR) AF: 0.271 AC: 4129 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3468

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5172

South Asian (SAS) AF: 0.227 AC: 1093 AN: 4818

European-Finnish (FIN) AF: 0.243 AC: 2569 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19256 AN: 67982

Other (OTH) AF: 0.173 AC: 365 AN: 2112

Alfa AF: 0.251 Hom.: 17946

Bravo AF: 0.192

Asia WGS AF: 0.103 AC: 357 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	4.3
DANN	Benign	0.74
PhyloP100		-1.0
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: rs2799573; hg19: chr10-18601928;