10-18498463-C-G

Variant names:

• chr10-18498463-C-G
• rs1554831400
• NM_201596.3:c.442C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_201596.3(CACNB2):​c.442C>G​(p.Leu148Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L148L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• Publications: 0 publications found

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]

CACNB2 Gene-Disease associations (from GenCC):

• Brugada syndrome 4

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.442C>G	p.Leu148Val	missense_variant	Exon 4 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.280C>G	p.Leu94Val	missense_variant	Exon 3 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.442C>G	p.Leu148Val	missense_variant	Exon 4 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.280C>G	p.Leu94Val	missense_variant	Exon 3 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Oct 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 537371). 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 expected to disrupt CACNB2 protein function. 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. This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the CACNB2 protein (p.Leu94Val). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D;.;T;.;.;.;T;T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.9	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D;N;.;.;D;.;.;D;D;D;.;D;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;T;.;.;D;.;.;D;D;D;.;D;.;.
Sift4G	Uncertain	0.0020	D;D;T;.;.;D;T;D;D;D;D;D;D;.;.
Polyphen		0.86	P;D;D;.;.;P;.;.;.;D;P;P;.;.;.
Vest4		0.93
MutPred		0.55		Gain of methylation at K151 (P = 0.0963);Gain of methylation at K151 (P = 0.0963);Gain of methylation at K151 (P = 0.0963);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		0.79
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.67
gMVP		0.58
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1554831400; hg19: chr10-18787392;