10-18506518-G-C

Variant names:

• chr10-18506518-G-C
• rs149253719
• NM_201596.3:c.641G>C

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.641G>C​(p.Ser214Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,611,704 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S214N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 7.03
• Publications: 15 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• cardiogenetic disease

  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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.01582411).
• BP6: Variant 10-18506518-G-C is Benign according to our data. Variant chr10-18506518-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161211.
• BS2: High AC in GnomAd4 at 133 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.641G>C	p.Ser214Thr	missense	Exon 6 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201590.3	MANE Plus Clinical	c.479G>C	p.Ser160Thr	missense	Exon 5 of 13	NP_963884.2	Q08289-3
	CACNB2	NM_201597.3		c.641G>C	p.Ser214Thr	missense	Exon 6 of 14	NP_963891.1	Q08289-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.641G>C	p.Ser214Thr	missense	Exon 6 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.479G>C	p.Ser160Thr	missense	Exon 5 of 13	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000352115.10	TSL:1	c.641G>C	p.Ser214Thr	missense	Exon 6 of 14	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00100 AC: 251 AN: 250608 AF XY: 0.00116

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1459376 Hom.: 6 Cov.: 29 AF XY: 0.00109 AC XY: 793 AN XY: 726198

African (AFR) AF: 0.000239 AC: 8 AN: 33424

American (AMR) AF: 0.000671 AC: 30 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86196

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53394

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5760

European-Non Finnish (NFE) AF: 0.00118 AC: 1315 AN: 1109878

Other (OTH) AF: 0.00104 AC: 63 AN: 60304

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74488

African (AFR) AF: 0.000289 AC: 12 AN: 41586

American (AMR) AF: 0.00163 AC: 25 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000986 Hom.: 0

Bravo AF: 0.000756

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000988 AC: 120

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Brugada syndrome 4 (3)
-	-	3	not provided (3)
-	2	1	not specified (3)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Early repolarization associated with ventricular fibrillation (1)
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.69	N
PhyloP100		7.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.39
MVP		0.84
MPC		0.29
ClinPred		0.025	T
GERP RS		5.9
Varity_R		0.34
gMVP		0.29
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs149253719; hg19: chr10-18795447; COSMIC: COSV56637041;