Menu
GeneBe

rs1555731992

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2_SupportingPP3_StrongPP5_Moderate

The NM_001127222(CACNA1A):c.5941-2A>G variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222 splice_acceptor

Scores

3
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.63

Links

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.014492754 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.7, offset of 24, new splice context is: ggacacccctcatgttccAGcgc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 19:13212742-T>C is Pathogenic according to our data. Variant chr19-13212742-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522037. 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.5941-2A>G splice_acceptor_variant ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.5941-2A>G splice_acceptor_variant 1 NM_001127222.2 O00555-8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.54e-7
AC:
1
AN:
1325966
Hom.:
0
AF XY:
0.00000155
AC XY:
1
AN XY:
647196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.62e-7
Gnomad4 OTH exome
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Benign
-0.20
Cadd
Pathogenic
34
Dann
Uncertain
0.98
Eigen
Pathogenic
0.88
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D;D
GERP RS
4.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.89
DS_AG_spliceai
0.71
Position offset: -26
DS_AL_spliceai
0.99
Position offset: -2
DS_DG_spliceai
0.0
Position offset: -26
DS_DL_spliceai
0.0
Position offset: -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: rs1555731992; hg19: chr19-13323556;