rs4664511

Variant names:

• chr2-151957950-G-A
• rs4664511
• NM_000726.5:c.148-74580C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

CACNB4 Gene-Disease associations (from GenCC):

• episodic ataxia type 5

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283228 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CACNB4	NM_000726.5	c.148-74580C>T		intron_variant	Intron 2 of 13	ENST00000539935.7	NP_000717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7	c.148-74580C>T		intron_variant	Intron 2 of 13	1	NM_000726.5	ENSP00000438949.1
ENSG00000283228	ENST00000637559.1	n.45+15719C>T		intron_variant	Intron 1 of 11	5		ENSP00000489697.1

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

African (AFR) AF: 0.833 AC: 34547 AN: 41494

American (AMR) AF: 0.735 AC: 11237 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.896 AC: 3110 AN: 3472

East Asian (EAS) AF: 0.287 AC: 1480 AN: 5152

South Asian (SAS) AF: 0.577 AC: 2777 AN: 4812

European-Finnish (FIN) AF: 0.880 AC: 9311 AN: 10586

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.914 AC: 62198 AN: 68030

Other (OTH) AF: 0.840 AC: 1775 AN: 2112

Alfa AF: 0.886 Hom.: 82138

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
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4664511; hg19: chr2-152814464;