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GeneBe

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

Scores

10
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

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
CACNA1ANM_001127222.2 linkuse as main transcriptc.2134G>T p.Ala712Ser missense_variant 17/47 ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.2134G>T p.Ala712Ser missense_variant 17/471 NM_001127222.2 O00555-8

Frequencies

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 providedclinical testingCytoplasmic Inheritance Laboratory, Institute of Genetics and CytologyOct 13, 2020We consider the variant NM_001127221.2:c.2137G>T as disease-causing; it results in an amino acid substitution. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.29
Cadd
Pathogenic
26
Dann
Uncertain
0.99
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.90
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
0.92
D
Sift4G
Uncertain
0.0030
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.76
MutPred
0.60
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
0.93
MPC
2.2
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.48
gMVP
0.96

Splicing

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: rs886037945; hg19: chr19-13414398;