10-18501574-G-A

Variant names:

• chr10-18501574-G-A
• rs12257556
• NM_201596.3:c.593+626G>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.593+626G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 152,082 control chromosomes in the GnomAD database, including 27,694 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 0.59 (27694 hom., cov: 33)
• Consequence: CACNB2 NM_201596.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743
• Publications: 5 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 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.593+626G>A		intron	N/A	NP_963890.2
	CACNB2	NM_201590.3	MANE Plus Clinical	c.431+626G>A		intron	N/A	NP_963884.2
	CACNB2	NM_201597.3		c.593+626G>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.593+626G>A		intron	N/A	ENSP00000320025.8
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.431+626G>A		intron	N/A	ENSP00000366546.4
	CACNB2	ENST00000352115.10	TSL:1	c.593+626G>A		intron	N/A	ENSP00000344474.6

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90316 AN: 151964 Hom.: 27648 Cov.: 33

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.689

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.588

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

GnomAD4 genome AF: 0.595 AC: 90417 AN: 152082 Hom.: 27694 Cov.: 33 AF XY: 0.598 AC XY: 44482 AN XY: 74346

African (AFR) AF: 0.683 AC: 28314 AN: 41484

American (AMR) AF: 0.599 AC: 9146 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1706 AN: 3472

East Asian (EAS) AF: 0.953 AC: 4939 AN: 5180

South Asian (SAS) AF: 0.690 AC: 3332 AN: 4828

European-Finnish (FIN) AF: 0.515 AC: 5440 AN: 10570

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.526 AC: 35748 AN: 67946

Other (OTH) AF: 0.582 AC: 1232 AN: 2116

Alfa AF: 0.537 Hom.: 36605

Bravo AF: 0.601

Asia WGS AF: 0.763 AC: 2649 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.63
PhyloP100		-0.74
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: rs12257556; hg19: chr10-18790503;