rs1554843116

Positions:

• chr10-18539589-G-GGACCACAAC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The ENST00000324631.13(CACNB2):​c.1851_1859dup​(p.Asp617_Asn619dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CACNB2 ENST00000324631.13 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000324631.13.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201590.3	c.1689_1697dup	p.Asp563_Asn565dup	inframe_insertion	13/13	ENST00000377329.10	NP_963884.2
CACNB2	NM_201596.3	c.1851_1859dup	p.Asp617_Asn619dup	inframe_insertion	14/14	ENST00000324631.13	NP_963890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1851_1859dup	p.Asp617_Asn619dup	inframe_insertion	14/14	1	NM_201596.3	ENSP00000320025
CACNB2	ENST00000377329.10	c.1689_1697dup	p.Asp563_Asn565dup	inframe_insertion	13/13	1	NM_201590.3	ENSP00000366546
	ENST00000425669.1	n.377-291_377-290insGTTGTGGTC		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2016

In summary, this is a novel sequence change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies investigating the functional effect of this duplication have not been published in the literature. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNB2-related disease. This sequence change inserts 9 nucleotides in exon 13 of the CACNB2 mRNA (c.1689_1697dupCCACAACGA). This leads to the insertion of 3 amino acid residue(s) in the CACNB2 protein (p.Asp563_Asn565dup) but otherwise preserves the integrity of the reading frame. -

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: rs1554843116; hg19: chr10-18828518;