rs149253719

Positions:

• chr10-18506518-G-A
• chr10-18506518-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_201596.3(CACNB2):​c.641G>A​(p.Ser214Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S214T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-18506518-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.17687419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.641G>A	p.Ser214Asn	missense_variant	6/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.479G>A	p.Ser160Asn	missense_variant	5/13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.641G>A	p.Ser214Asn	missense_variant	6/14	1	NM_201596.3	ENSP00000320025
CACNB2	ENST00000377329.10	c.479G>A	p.Ser160Asn	missense_variant	5/13	1	NM_201590.3	ENSP00000366546

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250608 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135532

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459396 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726204

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2021

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 160 of the CACNB2 protein (p.Ser160Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	T;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;.;T;T;T;T;T;T;T;T;.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-1.3	N;N;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.96	N;N;.;.;N;.;N;N;N;.;N;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.30	T;T;.;.;T;.;T;T;T;.;T;.;.
Sift4G	Benign	0.55	T;T;.;.;T;T;T;T;T;T;T;.;.
Polyphen		0.0010	B;B;.;.;B;.;.;B;B;B;.;.;.
Vest4		0.14
MutPred		0.31		Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.82
MPC		0.19
ClinPred		0.41	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149253719; hg19: chr10-18795447;