rs143326262

chr10-18539252-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_201596.3(CACNB2):c.1511C>T(p.Thr504Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,042 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T504T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (11 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11 O:1
• Conservation: PhyloP100: 0.904

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008203387).
• BP6: Variant 10-18539252-C-T is Benign according to our data. Variant chr10-18539252-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161212.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, not_provided=1, Benign=3, Uncertain_significance=1}. Variant chr10-18539252-C-T is described in Lovd as [Benign]. Variant chr10-18539252-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 253 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.1511C>T	p.Thr504Ile	missense_variant	14/14	ENST00000324631.13
CACNB2	NM_201590.3	c.1349C>T	p.Thr450Ile	missense_variant	13/13	ENST00000377329.10
LOC124902386	XR_007062076.1	n.25G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.1511C>T	p.Thr504Ile	missense_variant	14/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.1349C>T	p.Thr450Ile	missense_variant	13/13	1	NM_201590.3
	ENST00000425669.1	n.424G>A		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152078 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00148 AC: 373 AN: 251302 Hom.: 0 AF XY: 0.00153 AC XY: 208 AN XY: 135838

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00288 AC: 4214 AN: 1461846 Hom.: 11 Cov.: 31 AF XY: 0.00278 AC XY: 2022 AN XY: 727230

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152196 Hom.: 2 Cov.: 31 AF XY: 0.00142 AC XY: 106 AN XY: 74418

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00308 Hom.: 2

Bravo AF: 0.00168

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00157 AC: 191

EpiCase AF: 0.00316

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 proband in HGMD, ExAC: 0.2% (159/66588) European chromosomes -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2017	Variant summary: The CACNB2 c.1349C>T (p.Thr450Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 449/289284 control chromosomes (1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00279 (353/126520). This frequency is about 893 times the estimated maximal expected allele frequency of a pathogenic CACNB2 variant (0.0000031), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Though this variant has been reported in 2 individuals in a single family with BrS in an early study (Burashnikov 2010), later population studies indicated that the variant is not associated with BrS specific ECG patterns (Risgaard 2013, Ghouse 2017) and one study reports non-segregation of the variant with disease in a family (Allegue_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign. -

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	CACNB2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Uncertain significance and reported on 11-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Brugada syndrome 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Brugada syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, BS2 -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2019

This alteration is classified as likely 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. -

Ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.094	T;.;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0082	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.90	L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.67	N;N;N;.;.;N;.;.;N;N;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.19	T;T;T;.;.;T;.;.;T;T;T;T;.
Sift4G	Benign	0.21	T;T;T;.;.;T;T;T;T;T;T;T;.
Polyphen		0.45	P;B;D;.;.;B;.;.;.;B;B;.;.
Vest4		0.050
MVP		0.88
MPC		0.22
ClinPred		0.011	T
GERP RS		3.6
Varity_R		0.086
gMVP		0.20

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: rs143326262; hg19: chr10-18828181;