2-151834090-A-G

Position:

• chr2-151834090-A-G

Variant summary

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

The ENST00000539935.7(CACNB4):​c.*5029T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 152,130 control chromosomes in the GnomAD database, including 570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (570 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNB4 ENST00000539935.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.279

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=-0.56).
• BP6: Variant 2-151834090-A-G is Benign according to our data. Variant chr2-151834090-A-G is described in ClinVar as [Benign]. Clinvar id is 331561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB4	NM_000726.5	c.*5029T>C		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.*5029T>C		3_prime_UTR_variant	14/14	1	NM_000726.5	ENSP00000438949

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9033 AN: 152012 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0577

Gnomad OTH AF: 0.0517

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.0593 AC: 9026 AN: 152130 Hom.: 570 Cov.: 32 AF XY: 0.0635 AC XY: 4724 AN XY: 74372

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0539

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0577

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0560 Hom.: 299

Bravo AF: 0.0539

Asia WGS AF: 0.216 AC: 748 AN: 3476

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.7
DANN	Benign	0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs16830412; hg19: chr2-152690604;