rs797045425

Variant names:

• chr2-152098962-G-A
• rs797045425
• NM_000726.5:c.50C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-152098962-G-A
• chr2-152098962-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000726.5(CACNB4):​c.50C>T​(p.Ser17Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000729 in 1,372,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S17C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CACNB4 NM_000726.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.26
• 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: G2P, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000225214 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.236321).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	NM_000726.5	MANE Select	c.50C>T	p.Ser17Phe	missense	Exon 1 of 14	NP_000717.2
	CACNB4	NM_001145798.2		c.50C>T	p.Ser17Phe	missense	Exon 1 of 13	NP_001139270.1
	CACNB4	NM_001005746.4		c.-313C>T		upstream_gene	N/A	NP_001005746.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.50C>T	p.Ser17Phe	missense	Exon 1 of 14	ENSP00000438949.1
	CACNB4	ENST00000201943.10	TSL:1	c.50C>T	p.Ser17Phe	missense	Exon 1 of 13	ENSP00000201943.5
	CACNB4	ENST00000427385.6	TSL:5	c.50C>T	p.Ser17Phe	missense	Exon 1 of 13	ENSP00000410978.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372278 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 676482

African (AFR) AF: 0.00 AC: 0 AN: 30046

American (AMR) AF: 0.00 AC: 0 AN: 28080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23592

East Asian (EAS) AF: 0.00 AC: 0 AN: 35182

South Asian (SAS) AF: 0.00 AC: 0 AN: 75826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4756

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069060

Other (OTH) AF: 0.00 AC: 0 AN: 56708

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.025	D
Polyphen		0.19	B
Vest4		0.46
MutPred		0.20		Loss of glycosylation at S17 (P = 0.0059)
MVP		0.83
MPC		0.79
ClinPred		0.65	D
GERP RS		3.7
PromoterAI		0.054	Neutral
Varity_R		0.26
gMVP		0.34
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs797045425; hg19: chr2-152955476;