rs34503140

Positions:

• chr10-18539535-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_201596.3(CACNB2):​c.1794T>C​(p.Ser598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,613,426 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (15 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (102 hom.)
• Consequence: CACNB2 NM_201596.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.384

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-18539535-T-C is Benign according to our data. Variant chr10-18539535-T-C is described in ClinVar as [Benign]. Clinvar id is 299566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18539535-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.384 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00852 (1291/151592) while in subpopulation SAS AF= 0.0337 (160/4752). AF 95% confidence interval is 0.0294. There are 15 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1291 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.1794T>C	p.Ser598=	synonymous_variant	14/14	ENST00000324631.13
CACNB2	NM_201590.3	c.1632T>C	p.Ser544=	synonymous_variant	13/13	ENST00000377329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.1794T>C	p.Ser598=	synonymous_variant	14/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.1632T>C	p.Ser544=	synonymous_variant	13/13	1	NM_201590.3
	ENST00000425669.1	n.377-236A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00850 AC: 1287 AN: 151474 Hom.: 15 Cov.: 30

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.00408

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00747 AC: 1877 AN: 251312 Hom.: 36 AF XY: 0.00877 AC XY: 1191 AN XY: 135820

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00877

Gnomad SAS exome AF: 0.0346

Gnomad FIN exome AF: 0.00518

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00352 AC: 5143 AN: 1461834 Hom.: 102 Cov.: 35 AF XY: 0.00446 AC XY: 3241 AN XY: 727218

Gnomad4 AFR exome AF: 0.0236

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.00449

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00852 AC: 1291 AN: 151592 Hom.: 15 Cov.: 30 AF XY: 0.00912 AC XY: 675 AN XY: 74046

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0113

Gnomad4 SAS AF: 0.0337

Gnomad4 FIN AF: 0.00408

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00326 Hom.: 1

Bravo AF: 0.00824

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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+	-	- -

Brugada syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.0
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs34503140; hg19: chr10-18828464;