10-18500795-T-G

Position:

• chr10-18500795-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201596.3(CACNB2):​c.457-17T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,609,150 control chromosomes in the GnomAD database, including 76,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7819 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69027 hom.)
• Consequence: CACNB2 NM_201596.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-18500795-T-G is Benign according to our data. Variant chr10-18500795-T-G is described in ClinVar as [Benign]. Clinvar id is 263262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18500795-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201590.3	c.295-17T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000377329.10	NP_963884.2
CACNB2	NM_201596.3	c.457-17T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000324631.13	NP_963890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.457-17T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201596.3	ENSP00000320025
CACNB2	ENST00000377329.10	c.295-17T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201590.3	ENSP00000366546

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47638 AN: 151980 Hom.: 7817 Cov.: 33

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0391

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.310

GnomAD3 exomes AF: 0.277 AC: 69274 AN: 250110 Hom.: 10674 AF XY: 0.270 AC XY: 36510 AN XY: 135266

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.0343

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.299 AC: 435785 AN: 1457052 Hom.: 69027 Cov.: 33 AF XY: 0.294 AC XY: 213248 AN XY: 725078

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.0421

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.318

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.313 AC: 47656 AN: 152098 Hom.: 7819 Cov.: 33 AF XY: 0.309 AC XY: 22958 AN XY: 74348

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.0392

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.306

Alfa AF: 0.297 Hom.: 5363

Bravo AF: 0.315

Asia WGS AF: 0.120 AC: 416 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Brugada syndrome 4 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.68
CADD	Benign	16
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4485000; hg19: chr10-18789724; COSMIC: COSV56616510; COSMIC: COSV56616510;