rs199714857

chr10-18539422-G-Achr10-18539422-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_201596.3(CACNB2):c.1681G>A(p.Glu561Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,032 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E561D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (2 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.06

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11377114).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.1681G>A	p.Glu561Lys	missense_variant	14/14	ENST00000324631.13
CACNB2	NM_201590.3	c.1519G>A	p.Glu507Lys	missense_variant	13/13	ENST00000377329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.1681G>A	p.Glu561Lys	missense_variant	14/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.1519G>A	p.Glu507Lys	missense_variant	13/13	1	NM_201590.3
	ENST00000425669.1	n.377-123C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152064 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251248 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1461850 Hom.: 2 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 30 AF XY: 0.0000941 AC XY: 7 AN XY: 74422

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 4 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 507 of the CACNB2 protein (p.Glu507Lys). This variant is present in population databases (rs199714857, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 575677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 02, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0111 - The inheritance pattern for this gene is unknown. An inheritance pattern has not been provided by OMIM and ClinGen dispute its association with Brugada syndrome. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (23 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has one VUS entry in ClinVar and has previously been classified as a VUS with low clinical relevance in a Brugada patient tested at VCGS. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The p.E507K variant (also known as c.1519G>A), located in coding exon 13 of the CACNB2 gene, results from a G to A substitution at nucleotide position 1519. The glutamic acid at codon 507 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a Brugada syndrome cohort (Di Resta C et al. Hum Mol Genet, 2015 Oct;24:5828-35). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.86	N;N;N;.;.;N;.;.;N;N;N;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.14	T;T;T;.;.;T;.;.;T;T;T;.;T;.
Sift4G	Benign	0.77	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.61	P;B;P;.;.;P;.;.;.;B;P;.;.;.
Vest4		0.24
MVP		0.85
MPC		0.31
ClinPred		0.089	T
GERP RS		5.9
Varity_R		0.16
gMVP		0.18

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: rs199714857; hg19: chr10-18828351;