rs184841813

Positions:

chr9-138058108-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2

The NM_000718.4(CACNA1B):c.4166G>A(p.Arg1389His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,613,754 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 1 hom. )

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000453 (69/152342) while in subpopulation AMR AF= 0.000849 (13/15310). AF 95% confidence interval is 0.000585. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1B	NM_000718.4 linkuse as main transcript	c.4166G>A	p.Arg1389His	missense_variant	28/47	ENST00000371372.6
CACNA1B	NM_001243812.2 linkuse as main transcript	c.4166G>A	p.Arg1389His	missense_variant	28/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1B	ENST00000371372.6 linkuse as main transcript	c.4166G>A	p.Arg1389His	missense_variant	28/47	5	NM_000718.4	P4	Q00975-1
CACNA1B	ENST00000371357.5 linkuse as main transcript	c.4169G>A	p.Arg1390His	missense_variant	28/46	5		A2
CACNA1B	ENST00000371363.5 linkuse as main transcript	c.4166G>A	p.Arg1389His	missense_variant	28/46	5		A2
CACNA1B	ENST00000277551.6 linkuse as main transcript	c.4166G>A	p.Arg1389His	missense_variant	28/47	5		A2	Q00975-2

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.000750

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000433

AC:

108

AN:

249298

Hom.:

AF XY:

0.000414

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000690

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000535

AC:

782

AN:

1461412

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000625

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000453

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.00143

AC:

ExAC

AF:

0.000380

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	CACNA1B: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1389 of the CACNA1B protein (p.Arg1389His). This variant is present in population databases (rs184841813, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CACNA1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 189196). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dystonia 23

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

.;.;D;D;.;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.43

T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.0

D;.;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Benign

0.042

D;.;D;D;D;D

Sift4G

Uncertain

0.020

D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;.;D

Vest4

0.70

MVP

0.98

MPC

1.9

ClinPred

0.37

GERP RS

5.3

Varity_R

0.51

gMVP

0.84

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