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

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.63

Links

CACNA1A (HGNC:1388):

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 linkuse as main transcript	c.5941-2A>G		splice_acceptor_variant		ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.5941-2A>G		splice_acceptor_variant		1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.54e-7

AC:

AN:

1325966

Hom.:

AF XY:

0.00000155

AC XY:

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 submitter

clinical testing

Ambry Genetics

Sep 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.20

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Pathogenic

0.88

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over