rs1456201116

Variant names:

• chr10-18534227-G-GGTAA
• rs1456201116
• NM_201596.3:c.1206+4_1206+7dupAGTA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The ENST00000324631.13(CACNB2):​c.1206_1206+1insGTAA variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,610,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CACNB2 ENST00000324631.13 splice_donor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 10.0

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):

LOC124902387 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.076651536 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: aagGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 10-18534227-G-GGTAA is Benign according to our data. Variant chr10-18534227-G-GGTAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191435.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1206+4_1206+7dupAGTA		splice_region_variant, intron_variant	Intron 11 of 13	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1044+4_1044+7dupAGTA		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1206_1206+1insGTAA		splice_donor_variant, intron_variant	Intron 11 of 13	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1044_1044+1insGTAA		splice_donor_variant, intron_variant	Intron 10 of 12	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251274 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1457882 Hom.: 0 Cov.: 29 AF XY: 0.000116 AC XY: 84 AN XY: 725576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000388

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000825 Hom.: 0

Bravo AF: 0.000102

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Dec 21, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CACNB2 c.1044+4_1044+7dupAGTA variant involves the duplication of 4 nucleotides in the 10th intron of the gene that is 4 nucleotides away from the exon-intron junction. One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts the variant introduces an SRp55 ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 55/277112 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.003941 (40/10150). This frequency is about 394 times the estimated maximal expected allele frequency of a pathogenic CACNB2 variant (0.00001), strongly suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Long QT syndrome Uncertain:1

Feb 26, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome 4 Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 28, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Cardiac arrhythmia Benign:1

Oct 22, 2012

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in BRUGADA panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1456201116; hg19: chr10-18823156;