rs794727411

chr19-13261526-C-Achr19-13261526-C-Gchr19-13261526-C-T

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

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.88

Links

CACNA1A (HGNC:1388):

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
CACNA1A	NM_001127222.2 linkuse as main transcript	c.4174G>T	p.Val1392Leu	missense_variant	26/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.4174G>T	p.Val1392Leu	missense_variant	26/47	1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

Cov.:

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 submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Sep 09, 2020

This 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

BayesDel_noAF

Pathogenic

0.26

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

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

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.87

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

0.83

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over