chr10-18539706-T-C

Variant names:

• chr10-18539706-T-C
• rs58225473
• NM_201596.3:c.1965T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_201596.3(CACNB2):​c.1965T>C​(p.Asp655Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,608,556 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: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNB2 NM_201596.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.31
• Publications: 24 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-18539706-T-C is Benign according to our data. Variant chr10-18539706-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 698890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.31 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201596.3	MANE Select	c.1965T>C	p.Asp655Asp	synonymous	Exon 14 of 14	NP_963890.2
	CACNB2	NM_201590.3	MANE Plus Clinical	c.1803T>C	p.Asp601Asp	synonymous	Exon 13 of 13	NP_963884.2
	CACNB2	NM_201597.3		c.1893T>C	p.Asp631Asp	synonymous	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.1965T>C	p.Asp655Asp	synonymous	Exon 14 of 14	ENSP00000320025.8
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1803T>C	p.Asp601Asp	synonymous	Exon 13 of 13	ENSP00000366546.4
	CACNB2	ENST00000352115.10	TSL:1	c.1893T>C	p.Asp631Asp	synonymous	Exon 14 of 14	ENSP00000344474.6

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150442 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000331

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244118 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000894

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458114 Hom.: 0 Cov.: 42 AF XY: 0.00000138 AC XY: 1 AN XY: 725426

African (AFR) AF: 0.00 AC: 0 AN: 33186

American (AMR) AF: 0.0000455 AC: 2 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110996

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150442 Hom.: 0 Cov.: 29 AF XY: 0.0000273 AC XY: 2 AN XY: 73198

African (AFR) AF: 0.00 AC: 0 AN: 40892

American (AMR) AF: 0.000331 AC: 5 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67848

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 3971

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.8
DANN	Benign	0.79
PhyloP100		1.3

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: rs58225473; hg19: chr10-18828635;