rs61733967

Positions:

• chr10-18539526-C-T

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.1785C>T​(p.His595His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,866 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (19 hom., cov: 30)
  • Exomes 𝑓: 0.00077 (10 hom.)
• Consequence: CACNB2 NM_201596.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.71

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-18539526-C-T is Benign according to our data. Variant chr10-18539526-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18539526-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1226/152022) while in subpopulation AFR AF= 0.0283 (1172/41448). AF 95% confidence interval is 0.0269. There are 19 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1785C>T	p.His595His	synonymous_variant	14/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1623C>T	p.His541His	synonymous_variant	13/13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1785C>T	p.His595His	synonymous_variant	14/14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1623C>T	p.His541His	synonymous_variant	13/13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1222 AN: 151904 Hom.: 19 Cov.: 30

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00768

GnomAD3 exomes AF: 0.00206 AC: 518 AN: 251280 Hom.: 5 AF XY: 0.00144 AC XY: 195 AN XY: 135810

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000773 AC: 1130 AN: 1461844 Hom.: 10 Cov.: 35 AF XY: 0.000670 AC XY: 487 AN XY: 727224

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00806 AC: 1226 AN: 152022 Hom.: 19 Cov.: 30 AF XY: 0.00732 AC XY: 544 AN XY: 74308

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00760

Alfa AF: 0.00400 Hom.: 2

Bravo AF: 0.00840

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Aug 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 14, 2022	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2016	Variant summary: The c.1623C>T variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 5/5 in silico tools via Alamut predict no significant effect on splicing. This variant is found in 317/121328 control chromosomes (5 homozygotes) at a frequency of 0.0026128, which is about 261 times of maximal expected frequency of a pathogenic allele (0.00001), suggesting this variant is benign. In addition, one clinical laboratory classified this variant as benign. The variant of interest has been found in one individual with co-occurrence of KCNQ1 c.674C>T/p.S225L (pathogenic) in our laboratory. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/other clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CACNB2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 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	-0.52
CADD	Benign	1.5
DANN	Benign	0.90

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: rs61733967; hg19: chr10-18828455;