Menu
GeneBe

rs1555737113

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001127222.2(CACNA1A):c.5260G>A(p.Gly1754Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1754G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

10
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.78
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001127222.2
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, CACNA1A
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 19-13231850-C-T is Pathogenic according to our data. Variant chr19-13231850-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 476264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13231850-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.5260G>A p.Gly1754Arg missense_variant 35/47 ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.5260G>A p.Gly1754Arg missense_variant 35/471 NM_001127222.2 O00555-8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461096
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726794
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJun 13, 2022Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 476264). This missense change has been observed in individual(s) with generalized epilepsy with typical absence seizures (PMID: 26795593). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1755 of the CACNA1A protein (p.Gly1755Arg). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 16, 2015- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxApr 21, 2021Reported in a patient with a developmental disorder in published literature (Lecoquierre et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26795593, 28330790, 31036916) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
Cadd
Pathogenic
33
Dann
Uncertain
1.0
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
Sift4G
Pathogenic
0.0010
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.90
MutPred
0.82
.;.;Gain of MoRF binding (P = 0.0202);Gain of MoRF binding (P = 0.0202);Gain of MoRF binding (P = 0.0202);.;.;Gain of MoRF binding (P = 0.0202);.;.;.;Gain of MoRF binding (P = 0.0202);Gain of MoRF binding (P = 0.0202);.;Gain of MoRF binding (P = 0.0202);.;.;.;.;.;
MVP
0.97
MPC
2.6
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.74
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs1555737113; hg19: chr19-13342664; API