chr2-151870575-T-C

Variant names:

• chr2-151870575-T-C
• rs201870832
• NM_000726.5:c.655A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PVS1_Supporting BP6_Very_Strong BS2

The NM_001330114.2(CACNB4):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,613,932 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: CACNB4 NM_001330114.2 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.99
• Publications: 8 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: Benign. The variant received -11 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 19 codons. Genomic position: 151869226. Lost 0.061 part of the original CDS.
• BP6: Variant 2-151870575-T-C is Benign according to our data. Variant chr2-151870575-T-C is described in ClinVar as Benign. ClinVar VariationId is 136652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 370 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330114.2. 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.655A>G	p.Met219Val	missense	Exon 8 of 14	NP_000717.2	O00305-1
	CACNB4	NM_001330114.2		c.1A>G	p.Met1?	start_lost	Exon 7 of 13	NP_001317043.1
	CACNB4	NM_001005746.4		c.601A>G	p.Met201Val	missense	Exon 8 of 14	NP_001005746.1	O00305-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.655A>G	p.Met219Val	missense	Exon 8 of 14	ENSP00000438949.1	O00305-1
	CACNB4	ENST00000534999.7	TSL:1	c.553A>G	p.Met185Val	missense	Exon 7 of 13	ENSP00000443893.1	O00305-2
	CACNB4	ENST00000201943.10	TSL:1	c.655A>G	p.Met219Val	missense	Exon 8 of 13	ENSP00000201943.5	O00305-4

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152186 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000506 AC: 126 AN: 249062 AF XY: 0.000414

Gnomad AFR exome AF: 0.00698

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1461628 Hom.: 0 Cov.: 30 AF XY: 0.000202 AC XY: 147 AN XY: 727088

African (AFR) AF: 0.00828 AC: 277 AN: 33470

American (AMR) AF: 0.000537 AC: 24 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111832

Other (OTH) AF: 0.000398 AC: 24 AN: 60372

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152304 Hom.: 2 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74480

African (AFR) AF: 0.00832 AC: 346 AN: 41570

American (AMR) AF: 0.00105 AC: 16 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000745 Hom.: 1

Bravo AF: 0.00285

ESP6500AA AF: 0.00547 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000628 AC: 76

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	CACNB4-related disorder (1)
-	-	1	Idiopathic generalized epilepsy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.013	D
Sift4G	Benign	0.075	T
Polyphen		0.95	P
Vest4		0.84
MVP		0.91
MPC		1.6
ClinPred		0.037	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.81
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs201870832; hg19: chr2-152727089; COSMIC: COSV99071489; COSMIC: COSV99071489;