9-137878081-G-T

Position:

chr9-137878081-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000718.4(CACNA1B):c.148G>T(p.Ala50Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000066 in 151,514 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 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0 ( 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: 6.65

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 links:

ENSG00000203987 (HGNC:):

ENSG00000203987 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1B. . Gene score misZ 4.5165 (greater than the threshold 3.09). Trascript score misZ 3.231 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder with motor features, neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, undetermined early-onset epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.4144146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4 linkuse as main transcript	c.148G>T	p.Ala50Ser	missense_variant	1/47	ENST00000371372.6	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2 linkuse as main transcript	c.148G>T	p.Ala50Ser	missense_variant	1/47		NP_001230741.1	Q00975-2
LOC100133077	NR_121583.1 linkuse as main transcript	n.2692-2401C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1B	ENST00000371372.6 linkuse as main transcript	c.148G>T	p.Ala50Ser	missense_variant	1/47	5	NM_000718.4	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5 linkuse as main transcript	c.148G>T	p.Ala50Ser	missense_variant	1/46	5		ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5 linkuse as main transcript	c.148G>T	p.Ala50Ser	missense_variant	1/46	5		ENSP00000360414.1	B1AQK6
CACNA1B	ENST00000277551.6 linkuse as main transcript	c.148G>T	p.Ala50Ser	missense_variant	1/47	5		ENSP00000277551.2	Q00975-2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD3 exomes

AF:

0.0000130

AC:

AN:

231300

Hom.:

AF XY:

0.00000794

AC XY:

AN XY:

125898

show subpopulations

Gnomad AFR exome

AF:

0.000223

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

1190304

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

579170

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151514

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73988

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.148G>T (p.A50S) alteration is located in exon 1 (coding exon 1) of the CACNA1B gene. This alteration results from a G to T substitution at nucleotide position 148, causing the alanine (A) at amino acid position 50 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;.;T;T;.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.41

T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.;M;.;.;.

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-2.2

N;.;N;N;N;N

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0030

D;.;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;.;.

Vest4

0.43

MutPred

0.33

Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);

MVP

0.92

MPC

0.69

ClinPred

0.92

GERP RS

3.5

Varity_R

0.62

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over