2-151833734-G-A

Position:

• chr2-151833734-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000726.5(CACNB4):​c.*5385C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.934 in 152,124 control chromosomes in the GnomAD database, including 66,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66639 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CACNB4 NM_000726.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.83

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=-0.53).
• BP6: Variant 2-151833734-G-A is Benign according to our data. Variant chr2-151833734-G-A is described in ClinVar as [Benign]. Clinvar id is 331558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB4	NM_000726.5	c.*5385C>T		3_prime_UTR_variant	14/14	ENST00000539935.7	NP_000717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7	c.*5385C>T		3_prime_UTR_variant	14/14	1	NM_000726.5	ENSP00000438949

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142022 AN: 152006 Hom.: 66608 Cov.: 32

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.882

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.973

Gnomad OTH AF: 0.935

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.934 AC: 142102 AN: 152124 Hom.: 66639 Cov.: 32 AF XY: 0.934 AC XY: 69449 AN XY: 74366

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.969

Gnomad4 ASJ AF: 0.919

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.882

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.973

Gnomad4 OTH AF: 0.925

Alfa AF: 0.944 Hom.: 12039

Bravo AF: 0.931

Asia WGS AF: 0.822 AC: 2842 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile myoclonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Episodic ataxia type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1568673; hg19: chr2-152690248;