rs768612563

Variant names:

• chr2-151876421-C-T
• rs768612563
• NM_000726.5:c.521+5G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_000726.5(CACNB4):​c.521+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,595,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CACNB4 NM_000726.5 splice_region, intron
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283228 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000726.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	NM_000726.5	MANE Select	c.521+5G>A		splice_region intron	N/A	NP_000717.2	O00305-1
	CACNB4	NM_001005746.4		c.467+5G>A		splice_region intron	N/A	NP_001005746.1	O00305-3
	CACNB4	NM_001005747.4		c.419+5G>A		splice_region intron	N/A	NP_001005747.1	O00305-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.521+5G>A		splice_region intron	N/A	ENSP00000438949.1	O00305-1
	CACNB4	ENST00000534999.7	TSL:1	c.419+5G>A		splice_region intron	N/A	ENSP00000443893.1	O00305-2
	CACNB4	ENST00000201943.10	TSL:1	c.521+5G>A		splice_region intron	N/A	ENSP00000201943.5	O00305-4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000331 AC: 8 AN: 241514 AF XY: 0.0000305

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000901 AC: 13 AN: 1443548 Hom.: 0 Cov.: 30 AF XY: 0.00000975 AC XY: 7 AN XY: 718086

African (AFR) AF: 0.0000908 AC: 3 AN: 33036

American (AMR) AF: 0.00 AC: 0 AN: 43604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 38908

South Asian (SAS) AF: 0.0000477 AC: 4 AN: 83786

European-Finnish (FIN) AF: 0.0000757 AC: 4 AN: 52814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100614

Other (OTH) AF: 0.00 AC: 0 AN: 59460

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

African (AFR) AF: 0.000121 AC: 5 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.45
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.47		Position offset: 5

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

Other links and lift over

dbSNP: rs768612563; hg19: chr2-152732935;