rs16023

Positions:

Variant summary

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

The ENST00000360228.11(CACNA1A):c.2975A>T(p.Glu992Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,502,488 control chromosomes in the GnomAD database, including 15,900 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E992Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1408 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14492 hom. )

Consequence

CACNA1A
ENST00000360228.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 2.84

Variant links:

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A 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), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017878115).

BP6

Variant 19-13298658-T-A is Benign according to our data. Variant chr19-13298658-T-A is described in ClinVar as [Benign]. Clinvar id is 68427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298658-T-A is described in Lovd as [Benign]. Variant chr19-13298658-T-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.2975A>T	p.Glu992Val	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.2975A>T	p.Glu992Val	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20277

AN:

151782

Hom.:

1410

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.149

GnomAD3 exomes

AF:

0.137

AC:

14100

AN:

102910

Hom.:

1026

AF XY:

0.134

AC XY:

7629

AN XY:

57098

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.164

Gnomad EAS exome

AF:

0.0934

Gnomad SAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.148

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.144

AC:

194404

AN:

1350598

Hom.:

14492

Cov.:

AF XY:

0.144

AC XY:

95757

AN XY:

666138

show subpopulations

Gnomad4 AFR exome

AF:

0.0978

Gnomad4 AMR exome

AF:

0.147

Gnomad4 ASJ exome

AF:

0.163

Gnomad4 EAS exome

AF:

0.153

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.150

GnomAD4 genome

AF:

0.133

AC:

20272

AN:

151890

Hom.:

1408

Cov.:

AF XY:

0.132

AC XY:

9802

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.141

Gnomad4 ASJ

AF:

0.161

Gnomad4 EAS

AF:

0.123

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.151

Gnomad4 OTH

AF:

0.148

Alfa

AF:

0.145

Hom.:

532

Bravo

AF:

0.135

TwinsUK

AF:

0.138

AC:

512

ALSPAC

AF:

0.146

AC:

563

ESP6500AA

AF:

0.0930

AC:

230

ESP6500EA

AF:

0.128

AC:

655

ExAC

AF:

0.112

AC:

2507

Asia WGS

AF:

0.113

AC:

392

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.031

.;.;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.69

T;T;T;T;T;T;T;T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.1

.;.;.;.;L;.;.;.;.;.;.;.;L;.;.

MutationTaster

Benign

0.30

P;P;P

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.7

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.28

Sift

Uncertain

0.029

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.16

T;T;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.094

MPC

2.0

ClinPred

0.016

GERP RS

3.9

Varity_R

0.17

gMVP

0.52

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