chr19-13255130-T-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_001127222.2(CACNA1A):c.4720A>G(p.Met1574Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
CACNA1A
NM_001127222.2 missense
NM_001127222.2 missense
Scores
3
7
4
Clinical Significance
Conservation
PhyloP100: 3.11
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 Uncertain_significance. Variant got 5 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 where missense usually causes diseases, CACNA1A
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.4720A>G | p.Met1574Val | missense_variant | 29/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.4720A>G | p.Met1574Val | missense_variant | 29/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2020 | This sequence change replaces methionine with valine at codon 1575 of the CACNA1A protein (p.Met1575Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). 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. 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 not expected to disrupt CACNA1A protein function. This variant has not been reported in the literature in individuals with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 476261). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
0.34
.;.;Gain of catalytic residue at M1575 (P = 0.0146);Gain of catalytic residue at M1575 (P = 0.0146);Gain of catalytic residue at M1575 (P = 0.0146);.;.;Gain of catalytic residue at M1575 (P = 0.0146);.;.;Gain of catalytic residue at M1575 (P = 0.0146);Gain of catalytic residue at M1575 (P = 0.0146);.;Gain of catalytic residue at M1575 (P = 0.0146);.;Gain of catalytic residue at M1575 (P = 0.0146);.;
MVP
MPC
1.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at