rs144182966

Variant names:

• chr10-18539517-C-A
• rs144182966
• NM_201596.3:c.1776C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-18539517-C-A
• chr10-18539517-C-G
• chr10-18539517-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_201596.3(CACNB2):​c.1776C>A​(p.Asp592Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,940 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D592D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -3.49
• Publications: 7 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

ENSG00000240291 (HGNC:58168):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0151414275).
• BP6: Variant 10-18539517-C-A is Benign according to our data. Variant chr10-18539517-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161213.
• BS2: High AC in GnomAd4 at 55 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201596.3	MANE Select	c.1776C>A	p.Asp592Glu	missense	Exon 14 of 14	NP_963890.2
	CACNB2	NM_201590.3	MANE Plus Clinical	c.1614C>A	p.Asp538Glu	missense	Exon 13 of 13	NP_963884.2
	CACNB2	NM_201597.3		c.1704C>A	p.Asp568Glu	missense	Exon 14 of 14	NP_963891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.1776C>A	p.Asp592Glu	missense	Exon 14 of 14	ENSP00000320025.8
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1614C>A	p.Asp538Glu	missense	Exon 13 of 13	ENSP00000366546.4
	CACNB2	ENST00000352115.10	TSL:1	c.1704C>A	p.Asp568Glu	missense	Exon 14 of 14	ENSP00000344474.6

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 151968 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000438 AC: 110 AN: 251314 AF XY: 0.000501

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000722

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000447 AC: 653 AN: 1461854 Hom.: 3 Cov.: 35 AF XY: 0.000492 AC XY: 358 AN XY: 727226

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86258

European-Finnish (FIN) AF: 0.000505 AC: 27 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000482 AC: 536 AN: 1111982

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

GnomAD4 genome AF: 0.000362 AC: 55 AN: 152086 Hom.: 0 Cov.: 30 AF XY: 0.000269 AC XY: 20 AN XY: 74354

African (AFR) AF: 0.0000723 AC: 3 AN: 41500

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4778

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000454 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	2	not provided (2)
-	1	-	Brugada syndrome (1)
-	-	1	Brugada syndrome 4 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0020
DANN	Benign	0.91
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.28	N
PhyloP100		-3.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.13
Sift	Benign	0.48	T
Sift4G	Benign	0.47	T
Polyphen		0.0050	B
Vest4		0.049
MutPred		0.15		Gain of solvent accessibility (P = 0.0638)
MVP		0.46
MPC		0.19
ClinPred		0.022	T
GERP RS		-11
Varity_R		0.041
gMVP		0.028
Mutation Taster		=94/6	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: rs144182966; hg19: chr10-18828446;