19-13208879-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001127222.2(CACNA1A):c.6657T>C(p.His2219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,452,354 control chromosomes in the GnomAD database, including 247,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H2219HH) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.67 ( 33746 hom., cov: 27)

Exomes 𝑓: 0.61 ( 214122 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 19-13208879-A-G is Benign according to our data. Variant chr19-13208879-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13208879-A-G is described in Lovd as [Benign]. Variant chr19-13208879-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.6657T>C	p.His2219=	synonymous_variant	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.6657T>C	p.His2219=	synonymous_variant	46/47	1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.671

AC:

99644

AN:

148490

Hom.:

33711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.772

Gnomad AMI

AF:

0.603

Gnomad AMR

AF:

0.600

Gnomad ASJ

AF:

0.531

Gnomad EAS

AF:

0.787

Gnomad SAS

AF:

0.596

Gnomad FIN

AF:

0.739

Gnomad MID

AF:

0.435

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.609

GnomAD3 exomes

AF:

0.601

AC:

74602

AN:

124082

Hom.:

19596

AF XY:

0.599

AC XY:

40379

AN XY:

67406

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.562

Gnomad ASJ exome

AF:

0.520

Gnomad EAS exome

AF:

0.712

Gnomad SAS exome

AF:

0.575

Gnomad FIN exome

AF:

0.676

Gnomad NFE exome

AF:

0.599

Gnomad OTH exome

AF:

0.574

GnomAD4 exome

AF:

0.608

AC:

792867

AN:

1303764

Hom.:

214122

Cov.:

AF XY:

0.605

AC XY:

390146

AN XY:

644622

show subpopulations

Gnomad4 AFR exome

AF:

0.727

Gnomad4 AMR exome

AF:

0.558

Gnomad4 ASJ exome

AF:

0.523

Gnomad4 EAS exome

AF:

0.719

Gnomad4 SAS exome

AF:

0.567

Gnomad4 FIN exome

AF:

0.688

Gnomad4 NFE exome

AF:

0.606

Gnomad4 OTH exome

AF:

0.603

GnomAD4 genome

AF:

0.671

AC:

99736

AN:

148590

Hom.:

33746

Cov.:

AF XY:

0.675

AC XY:

48903

AN XY:

72412

show subpopulations

Gnomad4 AFR

AF:

0.773

Gnomad4 AMR

AF:

0.600

Gnomad4 ASJ

AF:

0.531

Gnomad4 EAS

AF:

0.787

Gnomad4 SAS

AF:

0.596

Gnomad4 FIN

AF:

0.739

Gnomad4 NFE

AF:

0.623

Gnomad4 OTH

AF:

0.611

Alfa

AF:

0.498

Hom.:

1245

Bravo

AF:

0.660

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Spinocerebellar ataxia type 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Episodic ataxia type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Jan 08, 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. -

Migraine, familial hemiplegic, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Apr 08, 2022

- -

Developmental and epileptic encephalopathy, 42

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

Cadd

Benign

6.6

Dann

Benign

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