rs1555740805

Variant summary

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

The NM_001127222.2(CACNA1A):​c.4897G>A​(p.Asp1633Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1633E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

13
4
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.87
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 repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 54 pathogenic changes around while only 11 benign (83%) in NM_001127222.2
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 19-13245235-C-T is Pathogenic according to our data. Variant chr19-13245235-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13245235-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.4897G>A p.Asp1633Asn missense_variant 31/47 ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.4897G>A p.Asp1633Asn missense_variant 31/471 NM_001127222.2 O00555-8

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterresearchMolecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella MarisJan 04, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 10, 2024The c.4900G>A (p.D1634N) alteration is located in coding exon 31 of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4900, causing the aspartic acid (D) at amino acid position 1634 to be replaced by an asparagine (N). ; however, it is unlikely to be causative of CACN1A-related spinocerebellar ataxia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or reported as heterozygous in multiple individuals with features consistent with episodic ataxia, type 2 and CACNA1A-related neurologic disorders (Galatolo, 2021; Courage, 2021; Lipman, 2022; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 24, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31785789, 29165669, 19344873, 33798445, 34445196) -
Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWendy Chung Laboratory, Columbia University Medical CenterMar 20, 2022- -
CACNA1A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 24, 2020The CACNA1A c.4900G>A (p.Asp1634Asn) variant is a missense variant. It is reported as a de novo variant, though without confirmed parentage, in one individual in the DECIPHER database (Firth et al. 2009, patient 259278). The reported phenotype of this individual is consistent with CACNA1A-related disorders and includes global developmental delay, intellectual disability, sleep disturbance, unsteady gait, falls, behavioral abnormalities, brachycephaly, strabismus, and bilateral single transverse palmar creases. The p.Asp1634Asn variant has also been identified by clinical laboratories in individuals with neurodevelopmental phenotypes consistent with CACNA1A-related disorders and submitted to the ClinVar database (Landrum et al. 2018); however these cases are not reported in the published literature and clinical details are limited. This variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. The p.Asp1634Asn variant occurs at a conserved residue in the S3 transmembrane segment of domain IV of the voltage-dependent P/Q-type calcium channel subunit alpha-1A protein, though the function of this region is unknown. In silico predictions suggest a damaging consequence, however this has not been evaluated experimentally. Based on the collective evidence and the application of ACMG criteria, the p.Asp1634Asn variant is classified as likely pathogenic for CACNA1A-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.5
.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.9
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.0040
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.96
MutPred
0.92
.;.;Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);.;.;Gain of MoRF binding (P = 0.1141);.;.;.;Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);.;Gain of MoRF binding (P = 0.1141);.;.;Gain of MoRF binding (P = 0.1141);.;
MVP
0.98
MPC
2.4
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.86
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1555740805; hg19: chr19-13356049; API