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
NM_001127222 splice_acceptor
Scores
3
2
2
Splicing: ADA: 1.000
2
Clinical Significance
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 |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.5941-2A>G | splice_acceptor_variant | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.5941-2A>G | splice_acceptor_variant | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomesCov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 7.54e-7 AC: 1AN: 1325966Hom.: 0 AF XY: 0.00000155 AC XY: 1AN XY: 647196
GnomAD4 exome
AF:
AC:
1
AN:
1325966
Hom.:
AF XY:
AC XY:
1
AN XY:
647196
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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 submitter | clinical testing | Ambry Genetics | Sep 29, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
DS_AG_spliceai
Position offset: -26
DS_AL_spliceai
Position offset: -2
DS_DG_spliceai
Position offset: -26
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at