rs147221323

Positions:

chr19-13207997-C-T

Variant summary

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

The ENST00000360228.11(CACNA1A):c.6837G>A(p.Pro2279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.046 in 1,327,418 control chromosomes in the GnomAD database, including 1,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 99 hom., cov: 29)

Exomes 𝑓: 0.048 ( 1593 hom. )

Consequence

CACNA1A
ENST00000360228.11 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.42

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 (MetaRNN=0.001943469).

BP6

Variant 19-13207997-C-T is Benign according to our data. Variant chr19-13207997-C-T is described in ClinVar as [Benign]. Clinvar id is 257512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13207997-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.42 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.6837G>A	p.Pro2279=	synonymous_variant	47/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.6837G>A	p.Pro2279=	synonymous_variant	47/47	1	NM_001127222.2	ENSP00000353362		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

4979

AN:

151182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00942

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0386

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00748

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.0511

Gnomad OTH

AF:

0.0371

GnomAD3 exomes

AF:

0.0492

AC:

702

AN:

14274

Hom.:

AF XY:

0.0484

AC XY:

363

AN XY:

7504

show subpopulations

Gnomad AFR exome

AF:

0.00851

Gnomad AMR exome

AF:

0.0452

Gnomad ASJ exome

AF:

0.0911

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0175

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0591

Gnomad OTH exome

AF:

0.0428

GnomAD4 exome

AF:

0.0477

AC:

56071

AN:

1176130

Hom.:

1593

Cov.:

AF XY:

0.0470

AC XY:

26636

AN XY:

566304

show subpopulations

Gnomad4 AFR exome

AF:

0.00714

Gnomad4 AMR exome

AF:

0.0348

Gnomad4 ASJ exome

AF:

0.0525

Gnomad4 EAS exome

AF:

0.000110

Gnomad4 SAS exome

AF:

0.00913

Gnomad4 FIN exome

AF:

0.0228

Gnomad4 NFE exome

AF:

0.0530

Gnomad4 OTH exome

AF:

0.0399

GnomAD4 genome

AF:

0.0329

AC:

4976

AN:

151288

Hom.:

Cov.:

AF XY:

0.0301

AC XY:

2222

AN XY:

73914

show subpopulations

Gnomad4 AFR

AF:

0.00939

Gnomad4 AMR

AF:

0.0385

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00748

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0511

Gnomad4 OTH

AF:

0.0367

Alfa

AF:

0.0449

Hom.:

Bravo

AF:

0.0346

ESP6500AA

AF:

0.00617

AC:

ESP6500EA

AF:

0.0338

AC:

217

ExAC

AF:

0.0107

AC:

882

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

-0.39

CADD

Benign

9.2

DANN

Benign

0.95

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0019

MutationTaster

Benign

1.0

D;D;D

GERP RS

0.42

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