Menu
GeneBe

rs794727411

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1PM1PM2_SupportingPM5PP2PP3_ModeratePP5_Moderate

The NM_001127222(CACNA1A):c.4174G>T(p.Val1392Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). 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)

Consequence

CACNA1A
NM_001127222 missense

Scores

7
6
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.88

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1
?
Transcript NM_001127222 (CACNA1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 280773
PM1
?
In a transmembrane_region Helical; Name=S5 of repeat III (size 19) in uniprot entity CAC1A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001127222
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
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 [Likely_pathogenic]. Clinvar id is 1285568. Status of the report is criteria_provided_single_submitter, 1 stars.

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

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
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). -

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
Uncertain
26
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

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;