NM_000726.5:c.147+3257T>C

Variant names:

• chr2-152095073-A-G
• rs10203659
• NM_000726.5:c.147+3257T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000726.5(CACNB4):​c.147+3257T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,110 control chromosomes in the GnomAD database, including 3,291 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 0.20 (3291 hom., cov: 32)
• Consequence: CACNB4 NM_000726.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB4	NM_000726.5	c.147+3257T>C		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.147+3257T>C		intron_variant	Intron 2 of 13	1	NM_000726.5	ENSP00000438949.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29687 AN: 151992 Hom.: 3276 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.195 AC: 29730 AN: 152110 Hom.: 3291 Cov.: 32 AF XY: 0.201 AC XY: 14961 AN XY: 74338

African (AFR) AF: 0.102 AC: 4236 AN: 41524

American (AMR) AF: 0.296 AC: 4517 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 810 AN: 3472

East Asian (EAS) AF: 0.259 AC: 1339 AN: 5164

South Asian (SAS) AF: 0.218 AC: 1048 AN: 4810

European-Finnish (FIN) AF: 0.305 AC: 3222 AN: 10554

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.203 AC: 13833 AN: 67994

Other (OTH) AF: 0.197 AC: 417 AN: 2114

Alfa AF: 0.199 Hom.: 573

Bravo AF: 0.194

Asia WGS AF: 0.271 AC: 940 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.79
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10203659; hg19: chr2-152951587;