NM_201596.3:c.333+43556G>A

Variant names:

• chr10-18445599-G-A
• rs17691888
• NM_201596.3:c.333+43556G>A

Variant summary

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

The NM_201596.3(CACNB2):​c.333+43556G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 93,324 control chromosomes in the GnomAD database, including 884 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 0.16 (884 hom., cov: 26)
• Consequence: CACNB2 NM_201596.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 15 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.26 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.333+43556G>A		intron	N/A	NP_963890.2
	CACNB2	NM_201590.3	MANE Plus Clinical	c.171+43556G>A		intron	N/A	NP_963884.2
	CACNB2	NM_201597.3		c.333+43556G>A		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.333+43556G>A		intron	N/A	ENSP00000320025.8
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.171+43556G>A		intron	N/A	ENSP00000366546.4
	CACNB2	ENST00000352115.10	TSL:1	c.333+43556G>A		intron	N/A	ENSP00000344474.6

Frequencies

GnomAD3 genomes AF: 0.158 AC: 14769 AN: 93212 Hom.: 882 Cov.: 26

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0891

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.158 AC: 14777 AN: 93324 Hom.: 884 Cov.: 26 AF XY: 0.162 AC XY: 7480 AN XY: 46132

African (AFR) AF: 0.0572 AC: 1765 AN: 30860

American (AMR) AF: 0.268 AC: 2604 AN: 9700

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 172 AN: 1452

East Asian (EAS) AF: 0.0884 AC: 441 AN: 4990

South Asian (SAS) AF: 0.185 AC: 535 AN: 2894

European-Finnish (FIN) AF: 0.221 AC: 1437 AN: 6498

Middle Eastern (MID) AF: 0.218 AC: 27 AN: 124

European-Non Finnish (NFE) AF: 0.212 AC: 7418 AN: 34976

Other (OTH) AF: 0.186 AC: 221 AN: 1190

Alfa AF: 0.0989 Hom.: 1246

Bravo AF: 0.0963

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.74
PhyloP100		0.29
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: rs17691888; hg19: chr10-18734528;