rs773391545

Variant names:

• chr2-152098386-T-G
• rs773391545
• NM_000726.5:c.91A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000726.5(CACNB4):​c.91A>C​(p.Ser31Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,613,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: CACNB4 NM_000726.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 5.00
• 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

ENSG00000225214 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22039494).
• BP6: Variant 2-152098386-T-G is Benign according to our data. Variant chr2-152098386-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446974.
• BS2: High AC in GnomAd4 at 12 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.91A>C	p.Ser31Arg	missense	Exon 2 of 14	NP_000717.2	O00305-1
	CACNB4	NM_001005746.4		c.37A>C	p.Ser13Arg	missense	Exon 2 of 14	NP_001005746.1	O00305-3
	CACNB4	NM_001145798.2		c.91A>C	p.Ser31Arg	missense	Exon 2 of 13	NP_001139270.1	O00305-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.91A>C	p.Ser31Arg	missense	Exon 2 of 14	ENSP00000438949.1	O00305-1
	CACNB4	ENST00000201943.10	TSL:1	c.91A>C	p.Ser31Arg	missense	Exon 2 of 13	ENSP00000201943.5	O00305-4
	CACNB4	ENST00000638005.1	TSL:2	c.37A>C	p.Ser13Arg	missense	Exon 2 of 14	ENSP00000489677.1	O00305-3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000844 AC: 21 AN: 248948 AF XY: 0.0000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000931 AC: 136 AN: 1461352 Hom.: 1 Cov.: 31 AF XY: 0.0000812 AC XY: 59 AN XY: 727014

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111614

Other (OTH) AF: 0.0000497 AC: 3 AN: 60352

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	CACNB4-related disorder (1)
-	1	-	Episodic ataxia type 5;C2750887:Epilepsy, idiopathic generalized, susceptibility to, 9 (1)
-	1	-	Idiopathic generalized epilepsy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.25
Sift	Benign	0.044	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.36
MutPred		0.11		Loss of phosphorylation at S31 (P = 0.0039)
MVP		0.88
MPC		1.7
ClinPred		0.29	T
GERP RS		5.1
PromoterAI		-0.070	Neutral
Varity_R		0.21
gMVP		0.90
Mutation Taster		=73/27	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs773391545; hg19: chr2-152954900;