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rs1555737113

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2_SupportingPP2PP3_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 was absent in control chromosomes in GnomAD Genomes project. 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 (★★).

Frequency

Genomes: not found (cov: 31)

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

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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; Number of alleles below threshold, Median coverage is 31.
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:
0.00000120
AC:
1
AN:
833104
Hom.:
0
AF XY:
0.00000260
AC XY:
1
AN XY:
384708
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:
0.00000131
Gnomad4 OTH exome
AF:
0.00

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, 2022This 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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 476264). Advanced 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. 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
29
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;