10-18500795-T-G

Variant names:

• chr10-18500795-T-G
• rs4485000
• NM_201596.3:c.457-17T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201596.3(CACNB2):​c.457-17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,609,150 control chromosomes in the GnomAD database, including 76,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7819 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69027 hom.)
• Consequence: CACNB2 NM_201596.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.15
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-18500795-T-G is Benign according to our data. Variant chr10-18500795-T-G is described in ClinVar as Benign. ClinVar VariationId is 263262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

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.457-17T>G		intron	N/A	NP_963890.2	Q08289-1
	CACNB2	NM_201590.3	MANE Plus Clinical	c.295-17T>G		intron	N/A	NP_963884.2	Q08289-3
	CACNB2	NM_201597.3		c.457-17T>G		intron	N/A	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.457-17T>G		intron	N/A	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.295-17T>G		intron	N/A	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000352115.10	TSL:1	c.457-17T>G		intron	N/A	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47638 AN: 151980 Hom.: 7817 Cov.: 33

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0391

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.277 AC: 69274 AN: 250110 AF XY: 0.270

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.0343

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.299 AC: 435785 AN: 1457052 Hom.: 69027 Cov.: 33 AF XY: 0.294 AC XY: 213248 AN XY: 725078

African (AFR) AF: 0.352 AC: 11754 AN: 33394

American (AMR) AF: 0.285 AC: 12747 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7723 AN: 26120

East Asian (EAS) AF: 0.0421 AC: 1670 AN: 39672

South Asian (SAS) AF: 0.131 AC: 11302 AN: 86214

European-Finnish (FIN) AF: 0.366 AC: 19343 AN: 52842

Middle Eastern (MID) AF: 0.260 AC: 1498 AN: 5762

European-Non Finnish (NFE) AF: 0.318 AC: 352747 AN: 1108108

Other (OTH) AF: 0.282 AC: 17001 AN: 60222

GnomAD4 genome AF: 0.313 AC: 47656 AN: 152098 Hom.: 7819 Cov.: 33 AF XY: 0.309 AC XY: 22958 AN XY: 74348

African (AFR) AF: 0.354 AC: 14683 AN: 41464

American (AMR) AF: 0.296 AC: 4527 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3468

East Asian (EAS) AF: 0.0392 AC: 203 AN: 5184

South Asian (SAS) AF: 0.125 AC: 602 AN: 4826

European-Finnish (FIN) AF: 0.370 AC: 3906 AN: 10566

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21578 AN: 67976

Other (OTH) AF: 0.306 AC: 646 AN: 2108

Alfa AF: 0.299 Hom.: 8324

Bravo AF: 0.315

Asia WGS AF: 0.120 AC: 416 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.70
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4485000; hg19: chr10-18789724; COSMIC: COSV56616510; COSMIC: COSV56616510;