rs143442080

Positions:

• chr2-151839382-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000726.5(CACNB4):​c.1303-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,600,440 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (19 hom.)
• Consequence: CACNB4 NM_000726.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004379
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.682

Genes affected

CACNB4 (HGNC:1404): (calcium voltage-gated channel auxiliary subunit beta 4) This gene encodes a member of the beta subunit family of voltage-dependent calcium channel complex proteins. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. The protein encoded by this locus plays an important role in calcium channel function by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Certain mutations in this gene have been associated with idiopathic generalized epilepsy (IGE), juvenile myoclonic epilepsy (JME), and episodic ataxia, type 5. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-151839382-A-G is Benign according to our data. Variant chr2-151839382-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151839382-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00249 (3609/1448100) while in subpopulation MID AF= 0.0262 (150/5730). AF 95% confidence interval is 0.0228. There are 19 homozygotes in gnomad4_exome. There are 1805 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 899 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB4	NM_000726.5	c.1303-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000539935.7	NP_000717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7	c.1303-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000726.5	ENSP00000438949

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 900 AN: 152222 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00380 AC: 932 AN: 245072 Hom.: 5 AF XY: 0.00376 AC XY: 501 AN XY: 133218

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.00507

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0000478

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00722

GnomAD4 exome AF: 0.00249 AC: 3609 AN: 1448100 Hom.: 19 Cov.: 28 AF XY: 0.00251 AC XY: 1805 AN XY: 720036

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.00542

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.000209

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152340 Hom.: 7 Cov.: 32 AF XY: 0.00612 AC XY: 456 AN XY: 74502

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00427 Hom.: 2

Bravo AF: 0.00685

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNB4: BP4, BS1, BS2 -

Juvenile myoclonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Episodic ataxia type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.046
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: rs143442080; hg19: chr2-152695896;