rs147857449

Positions:

• chr10-18534233-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201596.3(CACNB2):​c.1206+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,608,896 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (8 hom.)
• Consequence: CACNB2 NM_201596.3 splice_region, intron
• Scores: Splicing: ADA: 0.004505
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.157

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]

ENSG00000240291 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-18534233-T-C is Benign according to our data. Variant chr10-18534233-T-C is described in ClinVar as [Benign]. Clinvar id is 299560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18534233-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00536 (816/152342) while in subpopulation AFR AF= 0.0183 (760/41574). AF 95% confidence interval is 0.0172. There are 9 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 816 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1206+6T>C		splice_region_variant, intron_variant		ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1044+6T>C		splice_region_variant, intron_variant		ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1206+6T>C		splice_region_variant, intron_variant		1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1044+6T>C		splice_region_variant, intron_variant		1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152224 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00151 AC: 379 AN: 251214 Hom.: 4 AF XY: 0.00117 AC XY: 159 AN XY: 135808

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000633 AC: 922 AN: 1456554 Hom.: 8 Cov.: 29 AF XY: 0.000603 AC XY: 437 AN XY: 725036

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000921

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152342 Hom.: 9 Cov.: 33 AF XY: 0.00518 AC XY: 386 AN XY: 74486

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00295 Hom.: 4

Bravo AF: 0.00638

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.26
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0045
dbscSNV1_RF	Benign	0.094
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

Publications

LitVar

Other links and lift over

dbSNP: rs147857449; hg19: chr10-18823162;