10-18539442-C-T

Variant names:

• chr10-18539442-C-T
• rs2228645
• NM_201596.3:c.1701C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_201596.3(CACNB2):​c.1701C>T​(p.Tyr567Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,613,638 control chromosomes in the GnomAD database, including 29,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3194 hom., cov: 30)
  • Exomes 𝑓: 0.18 (26070 hom.)
• Consequence: CACNB2 NM_201596.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.61

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]

ENSG00000240291 (HGNC:58168):

LOC124902386 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-18539442-C-T is Benign according to our data. Variant chr10-18539442-C-T is described in ClinVar as [Benign]. Clinvar id is 263261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18539442-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1701C>T	p.Tyr567Tyr	synonymous_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1539C>T	p.Tyr513Tyr	synonymous_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1701C>T	p.Tyr567Tyr	synonymous_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1539C>T	p.Tyr513Tyr	synonymous_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29759 AN: 151762 Hom.: 3193 Cov.: 30

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.219 AC: 55096 AN: 251094 Hom.: 7070 AF XY: 0.216 AC XY: 29324 AN XY: 135718

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.295

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.180 AC: 263797 AN: 1461758 Hom.: 26070 Cov.: 36 AF XY: 0.183 AC XY: 133312 AN XY: 727172

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.262

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.196 AC: 29780 AN: 151880 Hom.: 3194 Cov.: 30 AF XY: 0.202 AC XY: 15003 AN XY: 74238

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.187

Alfa AF: 0.168 Hom.: 3931

Bravo AF: 0.199

Asia WGS AF: 0.304 AC: 1059 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.156

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome 4 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 18, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.38
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228645; hg19: chr10-18828371; COSMIC: COSV56616527; COSMIC: COSV56616527;