9-137878025-G-T

Position:

chr9-137878025-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000718.4(CACNA1B):c.92G>T(p.Gly31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 150,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00017 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.854

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:

(HGNC:):

links:

Genome browser will be placed here

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=0.0054852366).

BP6

Variant 9-137878025-G-T is Benign according to our data. Variant chr9-137878025-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1317163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137878025-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00436 (655/150358) while in subpopulation AFR AF= 0.0147 (607/41326). AF 95% confidence interval is 0.0137. There are 1 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 655 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNA1B	NM_000718.4 linkuse as main transcript	c.92G>T	p.Gly31Val	missense_variant	1/47	ENST00000371372.6	NP_000709.1
LOC100133077	NR_121583.1 linkuse as main transcript	n.2692-2345C>A		intron_variant, non_coding_transcript_variant
CACNA1B	NM_001243812.2 linkuse as main transcript	c.92G>T	p.Gly31Val	missense_variant	1/47		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6 linkuse as main transcript	c.92G>T	p.Gly31Val	missense_variant	1/47	5	NM_000718.4	ENSP00000360423	P4	Q00975-1
	ENST00000371390.1 linkuse as main transcript	n.2692-2345C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00437

AC:

657

AN:

150250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00192

Gnomad ASJ

AF:

0.000580

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00486

GnomAD3 exomes

AF:

0.0122

AC:

748

AN:

61328

Hom.:

AF XY:

0.0120

AC XY:

423

AN XY:

35120

show subpopulations

Gnomad AFR exome

AF:

0.0224

Gnomad AMR exome

AF:

0.00850

Gnomad ASJ exome

AF:

0.00990

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000166

AC:

186

AN:

1118290

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

AN XY:

539428

show subpopulations

Gnomad4 AFR exome

AF:

0.00476

Gnomad4 AMR exome

AF:

0.00120

Gnomad4 ASJ exome

AF:

0.000131

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000428

Gnomad4 OTH exome

AF:

0.000573

GnomAD4 genome

AF:

0.00436

AC:

655

AN:

150358

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

302

AN XY:

73418

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.00192

Gnomad4 ASJ

AF:

0.000580

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00481

Alfa

AF:

0.00788

Hom.:

ExAC

AF:

0.00221

AC:

193

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CACNA1B: PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;.;T;T;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.59

T;T;T;T;T;T

MetaRNN

Benign

0.0055

T;T;T;T;T;T

MetaSVM

Uncertain

0.058

MutationAssessor

Benign

0.58

N;.;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.1

N;.;N;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.025

D;.;T;T;T;T

Sift4G

Uncertain

0.022

D;D;D;D;D;D

Polyphen

0.012

.;.;.;B;.;.

Vest4

0.27

MPC

0.94

ClinPred

0.011

GERP RS

1.3

Varity_R

0.16

gMVP

0.38

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