9-137878028-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000718.4(CACNA1B):c.95C>T(p.Pro32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 150,200 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: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.734

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02997604).

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.95C>T	p.Pro32Leu	missense	Exon 1 of 47	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2		c.95C>T	p.Pro32Leu	missense	Exon 1 of 47	NP_001230741.1	Q00975-2
CACNA1B-AS2	NR_121583.1		n.2692-2348G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.95C>T	p.Pro32Leu	missense	Exon 1 of 47	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5	TSL:5	c.95C>T	p.Pro32Leu	missense	Exon 1 of 46	ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5	TSL:5	c.95C>T	p.Pro32Leu	missense	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000150

AC:

AN:

66468

AF XY:

0.0000264

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:

0.000594

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000125

AC:

AN:

1121348

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

540996

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22682

American (AMR)

AF:

0.00

AC:

AN:

10188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15416

East Asian (EAS)

AF:

0.0000406

AC:

AN:

24614

South Asian (SAS)

AF:

0.0000345

AC:

AN:

28990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4248

European-Non Finnish (NFE)

AF:

0.0000128

AC:

AN:

935522

Other (OTH)

AF:

0.00

AC:

AN:

43862

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000601081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.329

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

AF:

0.0000133

AC:

AN:

150200

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73248

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41220

American (AMR)

AF:

0.00

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67262

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000205

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.030

MetaSVM

Uncertain

0.052

MutationAssessor

Benign

0.34

PhyloP100

0.73

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.35

Sift

Benign

0.033

Sift4G

Benign

0.46

Polyphen

0.0070

Vest4

0.28

MutPred

0.27

Loss of glycosylation at P32 (P = 0.0254)

MVP

0.70

MPC

0.79

ClinPred

0.097

GERP RS

0.89

PromoterAI

0.0040

Neutral

(source)

Varity_R

0.095

gMVP

0.32

Mutation Taster

=65/35

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over