10-18150882-G-A

Variant names:

• chr10-18150882-G-A
• rs875989812
• NM_201596.3:c.121-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_201596.3(CACNB2):​c.121-1G>A variant causes a splice acceptor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNB2 NM_201596.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• cardiogenetic disease

  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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.046898637 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201596.3	MANE Select	c.121-1G>A		splice_acceptor intron	N/A	NP_963890.2	Q08289-1
	CACNB2	NM_201597.3		c.121-1G>A		splice_acceptor intron	N/A	NP_963891.1	Q08289-8
	CACNB2	NM_201571.4		c.37-1G>A		splice_acceptor intron	N/A	NP_963865.2	Q08289-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.121-1G>A		splice_acceptor intron	N/A	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000352115.10	TSL:1	c.121-1G>A		splice_acceptor intron	N/A	ENSP00000344474.6	Q08289-8
	CACNB2	ENST00000282343.13	TSL:1	c.37-1G>A		splice_acceptor intron	N/A	ENSP00000282343.8	Q08289-4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 24994 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000101 AC: 3 AN: 295836 Hom.: 0 Cov.: 8 AF XY: 0.0000193 AC XY: 3 AN XY: 155844

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7814

American (AMR) AF: 0.00 AC: 0 AN: 11488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8104

East Asian (EAS) AF: 0.00 AC: 0 AN: 16968

South Asian (SAS) AF: 0.0000723 AC: 1 AN: 13834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1114

European-Non Finnish (NFE) AF: 0.00000984 AC: 2 AN: 203348

Other (OTH) AF: 0.00 AC: 0 AN: 14502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000468493), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 25020 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11758

African (AFR) AF: 0.00 AC: 0 AN: 6170

American (AMR) AF: 0.00 AC: 0 AN: 2472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 790

East Asian (EAS) AF: 0.00 AC: 0 AN: 634

South Asian (SAS) AF: 0.00 AC: 0 AN: 806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12892

Other (OTH) AF: 0.00 AC: 0 AN: 342

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.4
GERP RS		5.7
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 14
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs875989812; hg19: chr10-18439811;