NM_201596.3:c.84C>G

Variant names:

• chr10-18140820-C-G
• rs763573123
• NM_201596.3:c.84C>G

Variant summary

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

The NM_201596.3(CACNB2):​c.84C>G​(p.Asn28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N28N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• 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: 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

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.84C>G	p.Asn28Lys	missense	Exon 1 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201597.3		c.84C>G	p.Asn28Lys	missense	Exon 1 of 14	NP_963891.1	Q08289-8
	CACNB2	NM_201593.3		c.84C>G	p.Asn28Lys	missense	Exon 1 of 14	NP_963887.2	Q08289-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.84C>G	p.Asn28Lys	missense	Exon 1 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000352115.10	TSL:1	c.84C>G	p.Asn28Lys	missense	Exon 1 of 14	ENSP00000344474.6	Q08289-8
	CACNB2	ENST00000377328.5	TSL:1	c.84C>G	p.Asn28Lys	missense	Exon 1 of 7	ENSP00000366545.1	A6PVM6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452006 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721348

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.00 AC: 0 AN: 84582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108934

Other (OTH) AF: 0.00 AC: 0 AN: 59940

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.11
Sift	Uncertain	0.026	D
Sift4G	Benign	0.57	T
Polyphen		0.19	B
Vest4		0.59
MutPred		0.37		Gain of ubiquitination at N28 (P = 0.0128)
MVP		0.74
MPC		0.25
ClinPred		0.24	T
GERP RS		1.7
PromoterAI		-0.077	Neutral
Varity_R		0.13
gMVP		0.17
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763573123; hg19: chr10-18429749;