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

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.16

Links

CACNA1A (HGNC:1388):

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
CACNA1A	NM_001127222.2 linkuse as main transcript	c.2134G>T	p.Ala712Ser	missense_variant	17/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.2134G>T	p.Ala712Ser	missense_variant	17/47	1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

Cov.:

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 provided

clinical testing

Cytoplasmic Inheritance Laboratory, Institute of Genetics and Cytology

Oct 13, 2020

We 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

BayesDel_noAF

Pathogenic

0.29

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.92

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

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.

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