rs16025

Positions:

chr19-13298576-C-T

Variant summary

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

The NM_001127222.2(CACNA1A):c.3057G>A(p.Arg1019=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,542,382 control chromosomes in the GnomAD database, including 16,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1541 hom., cov: 33)

Exomes 𝑓: 0.14 ( 14986 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.587

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 19-13298576-C-T is Benign according to our data. Variant chr19-13298576-C-T is described in ClinVar as [Benign]. Clinvar id is 128551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298576-C-T is described in Lovd as [Benign]. Variant chr19-13298576-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.587 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 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.3057G>A	p.Arg1019=	synonymous_variant	19/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.3057G>A	p.Arg1019=	synonymous_variant	19/47	1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21413

AN:

152046

Hom.:

1541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.154

GnomAD3 exomes

AF:

0.133

AC:

19330

AN:

145714

Hom.:

1365

AF XY:

0.130

AC XY:

10060

AN XY:

77532

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.141

Gnomad ASJ exome

AF:

0.161

Gnomad EAS exome

AF:

0.0925

Gnomad SAS exome

AF:

0.114

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.154

GnomAD4 exome

AF:

0.144

AC:

200665

AN:

1390220

Hom.:

14986

Cov.:

AF XY:

0.144

AC XY:

98689

AN XY:

685690

show subpopulations

Gnomad4 AFR exome

AF:

0.122

Gnomad4 AMR exome

AF:

0.147

Gnomad4 ASJ exome

AF:

0.164

Gnomad4 EAS exome

AF:

0.146

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.152

GnomAD4 genome

AF:

0.141

AC:

21423

AN:

152162

Hom.:

1541

Cov.:

AF XY:

0.139

AC XY:

10324

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.143

Gnomad4 ASJ

AF:

0.162

Gnomad4 EAS

AF:

0.123

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.151

Gnomad4 OTH

AF:

0.153

Alfa

AF:

0.148

Hom.:

922

Bravo

AF:

0.143

Asia WGS

AF:

0.120

AC:

416

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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)	Mar 18, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.4

DANN

Benign

0.91

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