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GeneBe

rs16024

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001127222.2(CACNA1A):c.3040G>A(p.Glu1014Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,541,592 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1014D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0054 ( 28 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

2
2
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:12

Conservation

PhyloP100: 3.49
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2
Missense variant where missense usually causes diseases, CACNA1A
BP4
Computational evidence support a benign effect (MetaRNN=0.0114197135).
BP6
Variant 19-13298593-C-T is Benign according to our data. Variant chr19-13298593-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194928.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=3}. Variant chr19-13298593-C-T is described in Lovd as [Benign]. Variant chr19-13298593-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (573/152266) while in subpopulation NFE AF= 0.00578 (393/68014). AF 95% confidence interval is 0.00531. There are 0 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High AC in GnomAd at 573 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.3040G>A p.Glu1014Lys missense_variant 19/47 ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.3040G>A p.Glu1014Lys missense_variant 19/471 NM_001127222.2 O00555-8

Frequencies

GnomAD3 genomes
AF:
0.00377
AC:
573
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00147
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.00563
Gnomad ASJ
AF:
0.00230
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000472
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00578
Gnomad OTH
AF:
0.00621
GnomAD3 exomes
AF:
0.00356
AC:
514
AN:
144488
Hom.:
1
AF XY:
0.00375
AC XY:
289
AN XY:
77066
show subpopulations
Gnomad AFR exome
AF:
0.000671
Gnomad AMR exome
AF:
0.00436
Gnomad ASJ exome
AF:
0.00232
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00112
Gnomad FIN exome
AF:
0.000772
Gnomad NFE exome
AF:
0.00605
Gnomad OTH exome
AF:
0.00545
GnomAD4 exome
AF:
0.00541
AC:
7523
AN:
1389326
Hom.:
28
Cov.:
32
AF XY:
0.00532
AC XY:
3645
AN XY:
685244
show subpopulations
Gnomad4 AFR exome
AF:
0.00107
Gnomad4 AMR exome
AF:
0.00479
Gnomad4 ASJ exome
AF:
0.00221
Gnomad4 EAS exome
AF:
0.0000294
Gnomad4 SAS exome
AF:
0.00109
Gnomad4 FIN exome
AF:
0.00102
Gnomad4 NFE exome
AF:
0.00633
Gnomad4 OTH exome
AF:
0.00551
GnomAD4 genome
AF:
0.00376
AC:
573
AN:
152266
Hom.:
0
Cov.:
32
AF XY:
0.00357
AC XY:
266
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00147
Gnomad4 AMR
AF:
0.00562
Gnomad4 ASJ
AF:
0.00230
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.000472
Gnomad4 NFE
AF:
0.00578
Gnomad4 OTH
AF:
0.00615
Alfa
AF:
0.00521
Hom.:
5
Bravo
AF:
0.00427
TwinsUK
AF:
0.00485
AC:
18
ALSPAC
AF:
0.00519
AC:
20
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00570
AC:
35
ExAC
AF:
0.00200
AC:
62

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:4
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024CACNA1A: PP2, PP3, BS1 -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 08, 2017- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncMar 08, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 31, 2017- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
not specified Benign:3
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 17, 2016This 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. -
Inborn genetic diseases Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 30, 2016- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 24, 2018This alteration is classified as likely benign based on a combination of the following: 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. -
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
CACNA1A-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 01, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Developmental and epileptic encephalopathy, 42 Benign:1
Likely benign, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 12, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.21
Cadd
Benign
21
Dann
Benign
0.88
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.52
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Benign
0.011
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.35
T
MutationTaster
Benign
0.72
D;D;D
PrimateAI
Pathogenic
0.85
D
Sift4G
Benign
0.33
T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.18
MVP
0.78
MPC
1.2
ClinPred
0.016
T
GERP RS
3.5
Varity_R
0.15
gMVP
0.34

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.

Other links and lift over

dbSNP: rs16024; hg19: chr19-13409407; API