rs561197163

chr10-18527610-G-Achr10-18527610-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.967G>A(p.Ala323Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,590 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A323S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (1 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 10.0

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=0.21957216).
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.967G>A	p.Ala323Thr	missense_variant	10/14	ENST00000324631.13
CACNB2	NM_201590.3	c.805G>A	p.Ala269Thr	missense_variant	9/13	ENST00000377329.10
LOC124902386	XR_007062076.1	n.84-8780C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.967G>A	p.Ala323Thr	missense_variant	10/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.805G>A	p.Ala269Thr	missense_variant	9/13	1	NM_201590.3
	ENST00000425669.1	n.482+11584C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251284 Hom.: 1 AF XY: 0.0000810 AC XY: 11 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461384 Hom.: 1 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74410

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000219

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the CACNB2 protein (p.Ala269Thr). This variant is present in population databases (rs561197163, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 537373). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 18, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

The p.A269T variant (also known as c.805G>A), located in coding exon 9 of the CACNB2 gene, results from a G to A substitution at nucleotide position 805. The alanine at codon 269 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 08, 2020

Variant summary: CACNB2 c.805G>A (p.Ala269Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251284 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 33-fold the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Brugada Syndrome phenotype (3.1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.805G>A in individuals affected with Brugada Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;.;.;.;.;T;.;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.8	D;D;.;.;D;.;D;D;D;D;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;.;.;D;.;D;D;D;D;.
Sift4G	Benign	0.069	T;T;.;.;T;T;T;T;T;T;.
Polyphen		1.0	D;D;.;.;D;.;.;D;D;.;.
Vest4		0.85
MVP		0.79
MPC		0.77
ClinPred		0.53	D
GERP RS		5.7
Varity_R		0.72
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs561197163; hg19: chr10-18816539; COSMIC: COSV99992451; COSMIC: COSV99992451;