rs41276886

Positions:

chr19-13317310-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127222.2(CACNA1A):c.1357G>A(p.Ala453Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00502 in 1,600,748 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 27 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.13

Variant links:

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.009932339).

BP6

Variant 19-13317310-C-T is Benign according to our data. Variant chr19-13317310-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 68420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13317310-C-T is described in Lovd as [Benign]. Variant chr19-13317310-C-T is described in Lovd as [Likely_benign]. Variant chr19-13317310-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00425 (647/152144) while in subpopulation NFE AF= 0.00544 (370/68008). AF 95% confidence interval is 0.00498. There are 5 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 647 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.1357G>A	p.Ala453Thr	missense_variant	11/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.1357G>A	p.Ala453Thr	missense_variant	11/47	1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.00426

AC:

647

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00544

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00447

AC:

1108

AN:

247928

Hom.:

AF XY:

0.00431

AC XY:

579

AN XY:

134484

show subpopulations

Gnomad AFR exome

AF:

0.000653

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000724

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.00534

Gnomad OTH exome

AF:

0.00600

GnomAD4 exome

AF:

0.00510

AC:

7391

AN:

1448604

Hom.:

Cov.:

AF XY:

0.00492

AC XY:

3532

AN XY:

717536

show subpopulations

Gnomad4 AFR exome

AF:

0.000751

Gnomad4 AMR exome

AF:

0.00106

Gnomad4 ASJ exome

AF:

0.000346

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000722

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.00547

Gnomad4 OTH exome

AF:

0.00378

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152144

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

347

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0174

Gnomad4 NFE

AF:

0.00544

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00468

Hom.:

Bravo

AF:

0.00319

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00106

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00440

AC:

532

EpiCase

AF:

0.00453

EpiControl

AF:

0.00333

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CACNA1A: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2017	- -
Likely benign, no assertion criteria provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 26, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC at a MaxMAF of 2% in Finnish chromosomes. It is classified in ClinVar with 1 star as Benign by Emory and Likely Benign by UniProtKB/Swiss-Prot. It was reported in one patient with alternating hemiplagia of childhood who also had a de novo variant in ATP1A3, CACNA1A variant was also seen in her unaffected mother. It was seen in one family with Familial hemiplegic migraine (segregated in 1 relative) and was associated with the absence of sensorimotor symptoms in a migraine with aura. In the same paper, authors show via in vitro studies that this variant affected protein function. Was also seen in one proband with early-onset progressive ataxia and her affected sister. If this variant plays any role in disease, its frequnecy is too high to be a Mendelian variant. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2014	- -

Episodic ataxia type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CACNA1A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

.;.;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0099

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.6

.;.;.;.;L;.;.;L;.;.;.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.8

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

REVEL

Uncertain

0.56

Sift

Benign

0.34

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.082

T;T;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.55

MVP

0.97

MPC

2.2

ClinPred

0.031

GERP RS

5.6

Varity_R

0.27

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over