Genetic Variant CACNA1B:p.Phe76Leu (chr9-137878161-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000718.4(CACNA1B):c.228C>A(p.Phe76Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.04

Publications

7 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
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:

CACNA1B-AS2 (HGNC:58213):

CACNA1B-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000718.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1B	NM_000718.4	MANE Select	c.228C>A	p.Phe76Leu	missense	Exon 1 of 47	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2		c.228C>A	p.Phe76Leu	missense	Exon 1 of 47	NP_001230741.1	Q00975-2
CACNA1B-AS2	NR_121583.1		n.2692-2481G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.228C>A	p.Phe76Leu	missense	Exon 1 of 47	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5	TSL:5	c.228C>A	p.Phe76Leu	missense	Exon 1 of 46	ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5	TSL:5	c.228C>A	p.Phe76Leu	missense	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000814

AC:

AN:

245602

AF XY:

0.00000748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1152904

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

555594

African (AFR)

AF:

0.00

AC:

AN:

24208

American (AMR)

AF:

0.00

AC:

AN:

13646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15414

East Asian (EAS)

AF:

0.00

AC:

AN:

27938

South Asian (SAS)

AF:

0.00

AC:

AN:

31314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

951636

Other (OTH)

AF:

0.00

AC:

AN:

45664

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Benign

0.13

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.6

PhyloP100

5.0

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.34

Sift

Benign

0.13

Sift4G

Benign

0.15

Polyphen

0.70

Vest4

0.62

MutPred

0.74

Loss of sheet (P = 0.1158)

MVP

0.64

MPC

0.78

ClinPred

0.92

GERP RS

3.5

PromoterAI

-0.078

Neutral

(source)

Varity_R

0.86

gMVP

0.77

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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