9-137877982-G-A

Position:

chr9-137877982-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000718.4(CACNA1B):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,130,022 control chromosomes in the GnomAD database, including 2,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 728 hom., cov: 33)

Exomes 𝑓: 0.16 ( 2175 hom. )

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.09

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.0010201633).

BP6

Variant 9-137877982-G-A is Benign according to our data. Variant chr9-137877982-G-A is described in ClinVar as [Benign]. Clinvar id is 1222494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/47	ENST00000371372.6	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/47		NP_001230741.1	Q00975-2
LOC100133077	NR_121583.1 linkuse as main transcript	n.2692-2302C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1B	ENST00000371372.6 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/47	5	NM_000718.4	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/46	5		ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/46	5		ENSP00000360414.1	B1AQK6
CACNA1B	ENST00000277551.6 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/47	5		ENSP00000277551.2	Q00975-2

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

19969

AN:

148528

Hom.:

732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0856

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.00471

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.154

Gnomad MID

AF:

0.112

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.131

GnomAD3 exomes

AF:

0.120

AC:

1260

AN:

10516

Hom.:

AF XY:

0.119

AC XY:

626

AN XY:

5240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.286

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.156

AC:

152903

AN:

981384

Hom.:

2175

Cov.:

AF XY:

0.157

AC XY:

72604

AN XY:

463456

show subpopulations

Gnomad4 AFR exome

AF:

0.0819

Gnomad4 AMR exome

AF:

0.199

Gnomad4 ASJ exome

AF:

0.193

Gnomad4 EAS exome

AF:

0.00358

Gnomad4 SAS exome

AF:

0.140

Gnomad4 FIN exome

AF:

0.178

Gnomad4 NFE exome

AF:

0.160

Gnomad4 OTH exome

AF:

0.150

GnomAD4 genome

AF:

0.134

AC:

19966

AN:

148638

Hom.:

728

Cov.:

AF XY:

0.134

AC XY:

9720

AN XY:

72486

show subpopulations

Gnomad4 AFR

AF:

0.0855

Gnomad4 AMR

AF:

0.167

Gnomad4 ASJ

AF:

0.160

Gnomad4 EAS

AF:

0.00473

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.154

Gnomad4 NFE

AF:

0.162

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.155

Hom.:

ExAC

AF:

0.0562

AC:

229

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CACNA1B-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;.;T;T;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

T;T;T;T;T;T

MetaRNN

Benign

0.0010

T;T;T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.3

L;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.49

T;T;T;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T;T

Polyphen

0.13

.;.;.;B;.;.

Vest4

0.12

MPC

1.5

ClinPred

0.031

GERP RS

2.6

Varity_R

0.053

gMVP

0.33

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

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