dbSNP rs1554758384: CACNA1B:p.Ser1745Gly (chr9-138102721-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000718.4(CACNA1B):c.5233A>G(p.Ser1745Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

Publications

0 publications found

Variant links:

Genes affected

CACNA1B (HGNC:1389): (calcium voltage-gated channel subunit alpha1 B) The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

CACNA1B Gene-Disease associations (from GenCC):

neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
complex neurodevelopmental disorder with motor features
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34095773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1B	NM_000718.4 link	c.5233A>G	p.Ser1745Gly	missense_variant	Exon 38 of 47	ENST00000371372.6	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2 link	c.5233A>G	p.Ser1745Gly	missense_variant	Exon 38 of 47		NP_001230741.1	Q00975-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1B	ENST00000371372.6 link	c.5233A>G	p.Ser1745Gly	missense_variant	Exon 38 of 47	5	NM_000718.4	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5 link	c.5230A>G	p.Ser1744Gly	missense_variant	Exon 37 of 46	5		ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5 link	c.5227A>G	p.Ser1743Gly	missense_variant	Exon 37 of 46	5		ENSP00000360414.1	B1AQK6
CACNA1B	ENST00000277551.6 link	c.5233A>G	p.Ser1745Gly	missense_variant	Exon 38 of 47	5		ENSP00000277551.2	Q00975-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

85950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109698

Other (OTH)

AF:

0.00

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonia 23

Uncertain:1

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

.;.;D;D;.;D

Eigen

Benign

-0.13

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.34

T;T;T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.3

L;.;L;.;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;.;N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.037

D;.;D;D;D;D

Sift4G

Benign

0.15

T;T;T;T;T;T

Polyphen

0.092

.;.;.;B;.;B

Vest4

0.45

MutPred

0.41

.;.;.;.;.;Loss of catalytic residue at S1744 (P = 0.0696);

MVP

0.88

MPC

1.3

ClinPred

0.62

GERP RS

4.7

Varity_R

0.16

gMVP

0.79

Mutation Taster

=80/20

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over