Menu
GeneBe

rs794727411

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM1PM5PP2PP3_ModeratePP5

The NM_001127222.2(CACNA1A):c.4174G>T(p.Val1392Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1392A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CACNA1A
NM_001127222.2 missense

Scores

7
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.88
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 12 ACMG points.

PS1
Transcript NM_001127222.2 (CACNA1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 280773
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001127222.2
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-13261525-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1522436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, CACNA1A
PP3
MetaRNN computational evidence supports a deleterious effect, 0.875
PP5
Variant 19-13261526-C-A is Pathogenic according to our data. Variant chr19-13261526-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1285568.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.4174G>T p.Val1392Leu missense_variant 26/47 ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.4174G>T p.Val1392Leu missense_variant 26/471 NM_001127222.2 O00555-8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
615648
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
334632
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterSep 09, 2020This variant was identified as de novo (maternity and paternity confirmed). -
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 24, 2022ClinVar contains an entry for this variant (Variation ID: 1285568). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1393 of the CACNA1A protein (p.Val1393Leu). 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. 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. This variant disrupts the p.Val1393 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28007337, 29056246, 29100083, 30283815, 31468518). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
Cadd
Pathogenic
28
Dann
Uncertain
0.99
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.87
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
0.83
D
Sift4G
Uncertain
0.051
T;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.79
MutPred
0.70
.;.;Loss of catalytic residue at V1393 (P = 0.038);Loss of catalytic residue at V1393 (P = 0.038);Loss of catalytic residue at V1393 (P = 0.038);.;Loss of catalytic residue at V1393 (P = 0.038);.;.;Loss of catalytic residue at V1393 (P = 0.038);Loss of catalytic residue at V1393 (P = 0.038);.;Loss of catalytic residue at V1393 (P = 0.038);.;Loss of catalytic residue at V1393 (P = 0.038);
MVP
0.94
MPC
2.2
ClinPred
0.98
D
GERP RS
4.3
Varity_R
0.41
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13372340; API