chr2-151833747-A-G

Position:

• chr2-151833747-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000726.5(CACNB4):​c.*5372T>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 0.00713 in 152,222 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CACNB4 NM_000726.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.252

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-151833747-A-G is Benign according to our data. Variant chr2-151833747-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 331559.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00713 (1085/152222) while in subpopulation AFR AF= 0.0242 (1006/41586). AF 95% confidence interval is 0.0229. There are 12 homozygotes in gnomad4. There are 480 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1085 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB4	NM_000726.5	c.*5372T>C		3_prime_UTR_variant	14/14	ENST00000539935.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB4	ENST00000539935.7	c.*5372T>C		3_prime_UTR_variant	14/14	1	NM_000726.5

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1083 AN: 152104 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00431

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: 0.00713 AC: 1085 AN: 152222 Hom.: 12 Cov.: 32 AF XY: 0.00645 AC XY: 480 AN XY: 74428

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00530 Hom.: 0

Bravo AF: 0.00828

Asia WGS AF: 0.00145 AC: 5 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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 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	-0.60
CADD	Benign	9.9
DANN	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs150406641; hg19: chr2-152690261;