rs4664511

Positions:

• chr2-151957950-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000726.5(CACNB4):​c.148-74580C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 152,144 control chromosomes in the GnomAD database, including 54,817 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.84 (54817 hom., cov: 32)
• Consequence: CACNB4 NM_000726.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.575

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB4	NM_000726.5	c.148-74580C>T		intron_variant		ENST00000539935.7	NP_000717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7	c.148-74580C>T		intron_variant		1	NM_000726.5	ENSP00000438949

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127496 AN: 152026 Hom.: 54800 Cov.: 32

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.896

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.914

Gnomad OTH AF: 0.852

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.838 AC: 127549 AN: 152144 Hom.: 54817 Cov.: 32 AF XY: 0.829 AC XY: 61655 AN XY: 74380

Gnomad4 AFR AF: 0.833

Gnomad4 AMR AF: 0.735

Gnomad4 ASJ AF: 0.896

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.577

Gnomad4 FIN AF: 0.880

Gnomad4 NFE AF: 0.914

Gnomad4 OTH AF: 0.840

Alfa AF: 0.890 Hom.: 61212

Bravo AF: 0.829

Asia WGS AF: 0.478 AC: 1667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.2
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4664511; hg19: chr2-152814464;