rs121917812

chr10-18539345-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_201596.3(CACNB2):c.1604C>T(p.Ser535Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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 (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 3.96

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3327601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.1604C>T	p.Ser535Leu	missense_variant	14/14	ENST00000324631.13
CACNB2	NM_201590.3	c.1442C>T	p.Ser481Leu	missense_variant	13/13	ENST00000377329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.1604C>T	p.Ser535Leu	missense_variant	14/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.1442C>T	p.Ser481Leu	missense_variant	13/13	1	NM_201590.3
	ENST00000425669.1	n.377-46G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251360 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 4 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 30, 2007	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The p.S481L variant (also known as c.1442C>T), located in coding exon 13 of the CACNB2 gene, results from a C to T substitution at nucleotide position 1442. The serine at codon 481 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Benign	-0.013
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.9	M;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.80	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;N;N;.;.;N;.;.;N;N;N;.;N;.
REVEL	Benign	0.29
Sift	Benign	0.19	T;T;T;.;.;T;.;.;T;T;T;.;T;.
Sift4G	Benign	0.34	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.31	B;P;D;.;.;B;.;.;.;B;B;.;.;.
Vest4		0.24
MutPred		0.47		Loss of phosphorylation at S535 (P = 0.0186);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.88
MPC		0.18
ClinPred		0.57	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917812; hg19: chr10-18828274; COSMIC: COSV104389573; COSMIC: COSV104389573;