rs886037945
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP2PP3_ModeratePP5
The NM_001127222(CACNA1A):c.2134G>T(p.Ala712Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A712T) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 29)
Consequence
CACNA1A
NM_001127222 missense
NM_001127222 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 6.16
Links
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001127222
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 29.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr19-13303584-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254268. 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, 0.897
PP5
?
Variant 19:13303584-C>A is Pathogenic according to our data. Variant chr19-13303584-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 997449. Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.2134G>T | p.Ala712Ser | missense_variant | 17/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.2134G>T | p.Ala712Ser | missense_variant | 17/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomesCov.: 29
GnomAD3 genomes
Cov.:
29
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 42 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Cytoplasmic Inheritance Laboratory, Institute of Genetics and Cytology | Oct 13, 2020 | We consider the variant NM_001127221.2:c.2137G>T as disease-causing; it results in an amino acid substitution. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at