10-18539557-C-G

Variant names:

• chr10-18539557-C-G
• rs61733968
• NM_201596.3:c.1816C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201596.3(CACNB2):​c.1816C>G​(p.Arg606Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0149 in 1,613,704 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R606P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 30)
  • Exomes 𝑓: 0.015 (182 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.05
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine
• Brugada syndrome 1

  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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0092638135).
• BP6: Variant 10-18539557-C-G is Benign according to our data. Variant chr10-18539557-C-G is described in ClinVar as Benign. ClinVar VariationId is 191569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1702/151858) while in subpopulation NFE AF = 0.0177 (1206/67950). AF 95% confidence interval is 0.0169. There are 12 homozygotes in GnomAd4. There are 855 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1702 AD,Unknown gene.

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.1816C>G	p.Arg606Gly	missense	Exon 14 of 14	NP_963890.2
	CACNB2	NM_201590.3	MANE Plus Clinical	c.1654C>G	p.Arg552Gly	missense	Exon 13 of 13	NP_963884.2
	CACNB2	NM_201597.3		c.1744C>G	p.Arg582Gly	missense	Exon 14 of 14	NP_963891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.1816C>G	p.Arg606Gly	missense	Exon 14 of 14	ENSP00000320025.8
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1654C>G	p.Arg552Gly	missense	Exon 13 of 13	ENSP00000366546.4
	CACNB2	ENST00000352115.10	TSL:1	c.1744C>G	p.Arg582Gly	missense	Exon 14 of 14	ENSP00000344474.6

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1702 AN: 151742 Hom.: 12 Cov.: 30

Gnomad AFR AF: 0.00320

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.00681

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00911 AC: 2288 AN: 251274 AF XY: 0.00900

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0153 AC: 22325 AN: 1461846 Hom.: 182 Cov.: 35 AF XY: 0.0148 AC XY: 10751 AN XY: 727222

African (AFR) AF: 0.00221 AC: 74 AN: 33478

American (AMR) AF: 0.00552 AC: 247 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00188 AC: 162 AN: 86258

European-Finnish (FIN) AF: 0.00532 AC: 284 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0186 AC: 20675 AN: 1111982

Other (OTH) AF: 0.0133 AC: 803 AN: 60390

GnomAD4 genome AF: 0.0112 AC: 1702 AN: 151858 Hom.: 12 Cov.: 30 AF XY: 0.0115 AC XY: 855 AN XY: 74192

African (AFR) AF: 0.00319 AC: 132 AN: 41384

American (AMR) AF: 0.0157 AC: 240 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00230 AC: 11 AN: 4778

European-Finnish (FIN) AF: 0.00681 AC: 72 AN: 10574

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1206 AN: 67950

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00581 Hom.: 1

Bravo AF: 0.0109

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.00918 AC: 1114

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0149

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Brugada syndrome 4 (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0039240:Supraventricular tachycardia;C0042514:Ventricular tachycardia;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.036	D
Polyphen		0.96	D
Vest4		0.40
MVP		0.88
MPC		0.59
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.093
gMVP		0.083
Mutation Taster		=98/2	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: rs61733968; hg19: chr10-18828486;