NM_000726.5:c.1303-3T>C

Variant names:

• chr2-151839382-A-G
• rs143442080
• NM_000726.5:c.1303-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000726.5(CACNB4):​c.1303-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,600,440 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (19 hom.)
• Consequence: CACNB4 NM_000726.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004379
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.682
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-151839382-A-G is Benign according to our data. Variant chr2-151839382-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00249 (3609/1448100) while in subpopulation MID AF = 0.0262 (150/5730). AF 95% confidence interval is 0.0228. There are 19 homozygotes in GnomAdExome4. There are 1805 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 899 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.1303-3T>C		splice_region intron	N/A	NP_000717.2
	CACNB4	NM_001005746.4		c.1249-3T>C		splice_region intron	N/A	NP_001005746.1
	CACNB4	NM_001005747.4		c.1201-3T>C		splice_region intron	N/A	NP_001005747.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.1303-3T>C		splice_region intron	N/A	ENSP00000438949.1
	CACNB4	ENST00000534999.7	TSL:1	c.1201-3T>C		splice_region intron	N/A	ENSP00000443893.1
	CACNB4	ENST00000201943.10	TSL:1	c.1117-3T>C		splice_region intron	N/A	ENSP00000201943.5

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 900 AN: 152222 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00380 AC: 932 AN: 245072 AF XY: 0.00376

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.00507

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000478

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00722

GnomAD4 exome AF: 0.00249 AC: 3609 AN: 1448100 Hom.: 19 Cov.: 28 AF XY: 0.00251 AC XY: 1805 AN XY: 720036

African (AFR) AF: 0.0141 AC: 464 AN: 33010

American (AMR) AF: 0.00542 AC: 240 AN: 44284

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 453 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00291 AC: 250 AN: 85870

European-Finnish (FIN) AF: 0.000209 AC: 11 AN: 52514

Middle Eastern (MID) AF: 0.0262 AC: 150 AN: 5730

European-Non Finnish (NFE) AF: 0.00157 AC: 1726 AN: 1101470

Other (OTH) AF: 0.00527 AC: 315 AN: 59814

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152340 Hom.: 7 Cov.: 32 AF XY: 0.00612 AC XY: 456 AN XY: 74502

African (AFR) AF: 0.0133 AC: 553 AN: 41582

American (AMR) AF: 0.00752 AC: 115 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00198 AC: 135 AN: 68030

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00427 Hom.: 2

Bravo AF: 0.00685

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Episodic ataxia type 5 (1)
-	-	1	Idiopathic generalized epilepsy (1)
-	-	1	Juvenile myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.58
PhyloP100		0.68
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.046
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: rs143442080; hg19: chr2-152695896;