NM_201596.3:c.1054+7C>T

Variant names:

• chr10-18527704-C-T
• rs4314963
• NM_201596.3:c.1054+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201596.3(CACNB2):​c.1054+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,565,510 control chromosomes in the GnomAD database, including 29,134 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 0.20 (3200 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25934 hom.)
• Consequence: CACNB2 NM_201596.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004690
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.332
• Publications: 10 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

ENSG00000240291 (HGNC:58168):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-18527704-C-T is Benign according to our data. Variant chr10-18527704-C-T is described in ClinVar as Benign. ClinVar VariationId is 263263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1054+7C>T		splice_region_variant, intron_variant	Intron 10 of 13	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.892+7C>T		splice_region_variant, intron_variant	Intron 9 of 12	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1054+7C>T		splice_region_variant, intron_variant	Intron 10 of 13	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.892+7C>T		splice_region_variant, intron_variant	Intron 9 of 12	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29721 AN: 151958 Hom.: 3197 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.221 AC: 55255 AN: 249746 AF XY: 0.218

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.183 AC: 258839 AN: 1413432 Hom.: 25934 Cov.: 24 AF XY: 0.186 AC XY: 131097 AN XY: 706258

African (AFR) AF: 0.193 AC: 6273 AN: 32506

American (AMR) AF: 0.379 AC: 16908 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3845 AN: 25806

East Asian (EAS) AF: 0.293 AC: 11589 AN: 39516

South Asian (SAS) AF: 0.289 AC: 24671 AN: 85418

European-Finnish (FIN) AF: 0.187 AC: 9772 AN: 52302

Middle Eastern (MID) AF: 0.121 AC: 689 AN: 5682

European-Non Finnish (NFE) AF: 0.163 AC: 174679 AN: 1068766

Other (OTH) AF: 0.177 AC: 10413 AN: 58792

GnomAD4 genome AF: 0.196 AC: 29747 AN: 152078 Hom.: 3200 Cov.: 32 AF XY: 0.202 AC XY: 14995 AN XY: 74326

African (AFR) AF: 0.197 AC: 8156 AN: 41482

American (AMR) AF: 0.286 AC: 4361 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3470

East Asian (EAS) AF: 0.260 AC: 1342 AN: 5162

South Asian (SAS) AF: 0.299 AC: 1443 AN: 4824

European-Finnish (FIN) AF: 0.191 AC: 2026 AN: 10584

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11353 AN: 67972

Other (OTH) AF: 0.189 AC: 400 AN: 2112

Alfa AF: 0.175 Hom.: 1871

Bravo AF: 0.199

Asia WGS AF: 0.305 AC: 1060 AN: 3478

EpiCase AF: 0.166

EpiControl AF: 0.156

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Brugada syndrome 4 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.33
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0020
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: rs4314963; hg19: chr10-18816633; COSMIC: COSV56616514; COSMIC: COSV56616514;