chr10-18539574-C-T

Variant names:

• chr10-18539574-C-T
• rs777607595
• NM_201596.3:c.1833C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_201596.3(CACNB2):​c.1833C>T​(p.Asp611Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CACNB2 NM_201596.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.96
• Publications: 1 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

CACNB2-AS1 (HGNC:58168):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-18539574-C-T is Benign according to our data. Variant chr10-18539574-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.96 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 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.1833C>T	p.Asp611Asp	synonymous	Exon 14 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201590.3	MANE Plus Clinical	c.1671C>T	p.Asp557Asp	synonymous	Exon 13 of 13	NP_963884.2	Q08289-3
	CACNB2	NM_201597.3		c.1761C>T	p.Asp587Asp	synonymous	Exon 14 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.1833C>T	p.Asp611Asp	synonymous	Exon 14 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1671C>T	p.Asp557Asp	synonymous	Exon 13 of 13	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000352115.10	TSL:1	c.1761C>T	p.Asp587Asp	synonymous	Exon 14 of 14	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151548 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251230 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461858 Hom.: 0 Cov.: 35 AF XY: 0.0000289 AC XY: 21 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111990

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151548 Hom.: 0 Cov.: 30 AF XY: 0.0000271 AC XY: 2 AN XY: 73932

African (AFR) AF: 0.00 AC: 0 AN: 41202

American (AMR) AF: 0.000131 AC: 2 AN: 15218

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome 4 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.3
DANN	Benign	0.85
PhyloP100		2.0

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: rs777607595; hg19: chr10-18828503; COSMIC: COSV56628136; COSMIC: COSV56628136;