Genetic Variant NM_000726.5:c.44C>T (chr2-152098968-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000726.5(CACNB4):c.44C>T(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,376,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P15R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CACNB4
NM_000726.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.211

Publications

0 publications found

Variant links:

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

CACNB4 links:

ENSG00000225214 (HGNC:):

ENSG00000225214 links:

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ACMG classification

Classification was made for transcript

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=0.14848301).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNB4	NM_000726.5	MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 1 of 14	NP_000717.2
CACNB4	NM_001145798.2		c.44C>T	p.Pro15Leu	missense	Exon 1 of 13	NP_001139270.1
CACNB4	NM_001005746.4		c.-319C>T		upstream_gene	N/A	NP_001005746.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 1 of 14	ENSP00000438949.1
CACNB4	ENST00000201943.10	TSL:1	c.44C>T	p.Pro15Leu	missense	Exon 1 of 13	ENSP00000201943.5
CACNB4	ENST00000427385.6	TSL:5	c.44C>T	p.Pro15Leu	missense	Exon 1 of 13	ENSP00000410978.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.26e-7

AC:

AN:

1376974

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30156

American (AMR)

AF:

0.00

AC:

AN:

28554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23716

East Asian (EAS)

AF:

0.00

AC:

AN:

35132

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072504

Other (OTH)

AF:

0.00

AC:

AN:

56904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.10

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

-0.21

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

REVEL

Benign

0.18

Sift

Benign

0.35

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.17

MutPred

0.14

Gain of catalytic residue at P15 (P = 0.0042)

MVP

0.76

MPC

0.62

ClinPred

0.061

GERP RS

-0.083

PromoterAI

-0.067

Neutral

(source)

Varity_R

0.039

gMVP

0.34

Mutation Taster

=97/3

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over