chr2-151860809-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000726.5(CACNB4):c.770C>T(p.Thr257Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T257T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CACNB4
NM_000726.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB4	NM_000726.5 link	c.770C>T	p.Thr257Met	missense_variant	Exon 10 of 14	ENST00000539935.7	NP_000717.2	O00305-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7 link	c.770C>T	p.Thr257Met	missense_variant	Exon 10 of 14	1	NM_000726.5	ENSP00000438949.1		O00305-1
ENSG00000283228	ENST00000637559.1 link	n.598-5434C>T		intron_variant	Intron 7 of 11	5		ENSP00000489697.1		A0A1B0GTH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456076

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33338

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1106802

Other (OTH)

AF:

0.00

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy

Uncertain:1

Jan 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with CACNB4-related conditions. ClinVar contains an entry for this variant (Variation ID: 460001). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 257 of the CACNB4 protein (p.Thr257Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

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

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.93

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

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.

PhyloP100

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.7

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

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.035

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

Polyphen

1.0

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

Vest4

0.81

MutPred

0.84

Gain of loop (P = 0.0097);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of loop (P = 0.0097);.;

MVP

0.90

MPC

1.6

ClinPred

1.0

GERP RS

5.8

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.74

gMVP

0.92

Mutation Taster

=30/70

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over