Genetic Variant CACNB4:p.Cys104Ser (chr2-151880879-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000726.5(CACNB4):c.311G>C(p.Cys104Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C104F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNB4
NM_000726.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

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:

ENSG00000283228 (HGNC:):

ENSG00000283228 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB4	NM_000726.5 link	c.311G>C	p.Cys104Ser	missense_variant	Exon 4 of 14	ENST00000539935.7	NP_000717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7 link	c.311G>C	p.Cys104Ser	missense_variant	Exon 4 of 14	1	NM_000726.5	ENSP00000438949.1
ENSG00000283228	ENST00000637559.1 link	n.209G>C		non_coding_transcript_exon_variant	Exon 3 of 12	5		ENSP00000489697.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.082

T;.;.;T;T;.;T;T;.;.;T;T;.;.;T;.;.;T;.;T;T;T;.;.;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.74

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.31

N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.80

N;.;.;.;.;.;.;.;.;.;.;.;.;N;.;N;.;.;.;.;.;N;N;.;.;.

REVEL

Pathogenic

0.65

Sift

Benign

0.84

T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;T;T;.;.;.

Sift4G

Benign

0.69

T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;T;T;.;.;.

Vest4

0.87

ClinPred

0.96

GERP RS

5.4

PromoterAI

0.0082

Neutral

(source)

Varity_R

0.27

gMVP

0.76

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over