10-18527637-G-C

Variant names:

• chr10-18527637-G-C
• rs369543094
• NM_201596.3:c.994G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_201596.3(CACNB2):​c.994G>C​(p.Val332Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V332A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• cardiogenetic disease

  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

CACNB2-AS1 (HGNC:58168):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201596.3	MANE Select	c.994G>C	p.Val332Leu	missense	Exon 10 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201590.3	MANE Plus Clinical	c.832G>C	p.Val278Leu	missense	Exon 9 of 13	NP_963884.2	Q08289-3
	CACNB2	NM_201597.3		c.922G>C	p.Val308Leu	missense	Exon 10 of 14	NP_963891.1	Q08289-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.994G>C	p.Val332Leu	missense	Exon 10 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.832G>C	p.Val278Leu	missense	Exon 9 of 13	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000352115.10	TSL:1	c.922G>C	p.Val308Leu	missense	Exon 10 of 14	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.00083	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0087	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.0050	N
PhyloP100		10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.21	T
Sift4G	Benign	0.43	T
Polyphen		0.091	B
Vest4		0.77
MutPred		0.68		Gain of helix (P = 0.027)
MVP		0.56
MPC		0.78
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.28
gMVP		0.64
Mutation Taster		=53/47	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: rs369543094; hg19: chr10-18816566;