rs150722502

chr10-18150971-G-Achr10-18150971-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_201596.3(CACNB2):c.209G>A(p.Arg70His) variant causes a missense change. The variant allele was found at a frequency of 0.000973 in 1,568,760 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.14

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045506954).
• BP6: Variant 10-18150971-G-A is Benign according to our data. Variant chr10-18150971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 190713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18150971-G-A is described in Lovd as [Likely_benign]. Variant chr10-18150971-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.209G>A	p.Arg70His	missense_variant	2/14	ENST00000324631.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.209G>A	p.Arg70His	missense_variant	2/14	1	NM_201596.3

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 109 AN: 144244 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000579

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000594

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000773 AC: 194 AN: 251022 Hom.: 0 AF XY: 0.000833 AC XY: 113 AN XY: 135698

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000995 AC: 1417 AN: 1424406 Hom.: 1 Cov.: 28 AF XY: 0.000991 AC XY: 703 AN XY: 709514

Gnomad4 AFR exome AF: 0.0000924

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.000197

Gnomad4 EAS exome AF: 0.0000801

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.000701

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000821

GnomAD4 genome AF: 0.000755 AC: 109 AN: 144354 Hom.: 0 Cov.: 28 AF XY: 0.000661 AC XY: 46 AN XY: 69556

Gnomad4 AFR AF: 0.000203

Gnomad4 AMR AF: 0.000578

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000594

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000737

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000881 AC: 107

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28255936, 23861362) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

CACNB2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.046	T;T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.0	L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	D;N;N;.;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D;.;.;D
Sift4G	Benign	0.095	T;T;D;.;.;T
Polyphen		0.98	D;P;D;.;.;D
Vest4		0.93
MVP		0.89
MPC		0.61
ClinPred		0.086	T
GERP RS		5.9
Varity_R		0.22
gMVP		0.28

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: rs150722502; hg19: chr10-18439900; COSMIC: COSV56629541;