NM_201596.3:c.1017C>A

Variant names:

• chr10-18527660-C-A
• rs747015946
• NM_201596.3:c.1017C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_201596.3(CACNB2):​c.1017C>A​(p.His339Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H339H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.505
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36903673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1017C>A	p.His339Gln	missense_variant	Exon 10 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.855C>A	p.His285Gln	missense_variant	Exon 9 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1017C>A	p.His339Gln	missense_variant	Exon 10 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.855C>A	p.His285Gln	missense_variant	Exon 9 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461472 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60382

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

Dec 09, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence change replaces histidine with glutamine at codon 285 of the CACNB2 protein (p.His285Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNB2-related disease. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	1.4
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	T;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	-0.69	N;.;.;.;.;.;.;.;.;.;.
PhyloP100		-0.51
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.8	D;D;.;.;D;.;D;N;D;D;.
REVEL	Uncertain	0.56
Sift	Benign	0.050	D;D;.;.;D;.;D;T;T;T;.
Sift4G	Benign	0.076	T;T;.;.;T;T;T;T;T;T;.
Polyphen		0.38	B;B;.;.;B;.;.;D;B;.;.
Vest4		0.81
MutPred		0.45		Gain of solvent accessibility (P = 0.0374);.;.;.;.;.;.;.;.;.;.;
MVP		0.73
MPC		0.79
ClinPred		0.97	D
GERP RS		-5.5
Varity_R		0.28
gMVP		0.64
Mutation Taster		=24/76	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: rs747015946; hg19: chr10-18816589;