10-18539406-T-G

Variant names:

• chr10-18539406-T-G
• rs878855311
• NM_201596.3:c.1665T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_201596.3(CACNB2):​c.1665T>G​(p.Phe555Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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

ENSG00000240291 (HGNC:58168):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061478704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1665T>G	p.Phe555Leu	missense_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1503T>G	p.Phe501Leu	missense_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1665T>G	p.Phe555Leu	missense_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1503T>G	p.Phe501Leu	missense_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Mar 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 242262). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 501 of the CACNB2 protein (p.Phe501Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.068	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.87	D;D;D;.;D;D;D;D;D;D;D;T;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.061	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.44	N;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		1.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.76	N;N;N;.;.;N;.;.;N;N;N;.;N;.
REVEL	Benign	0.074
Sift	Benign	0.47	T;T;T;.;.;T;.;.;T;T;T;.;T;.
Sift4G	Benign	0.75	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.0010	B;B;B;.;.;B;.;.;.;B;B;.;.;.
Vest4		0.10
MutPred		0.16		Gain of MoRF binding (P = 0.1307);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.77
MPC		0.24
ClinPred		0.083	T
GERP RS		0.78
Varity_R		0.14
gMVP		0.082
Mutation Taster		=75/25	polymorphism

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: rs878855311; hg19: chr10-18828335;