Variant chr19-13453138-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.400-123G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 909,456 control chromosomes in the GnomAD database, including 6,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1539 hom., cov: 32)

Exomes 𝑓: 0.097 ( 4699 hom. )

Consequence

CACNA1A
NM_001127222.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.115

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 19-13453138-C-A is Benign according to our data. Variant chr19-13453138-C-A is described in ClinVar as [Benign]. Clinvar id is 680137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 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.400-123G>T		intron_variant		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.400-123G>T		intron_variant		1	NM_001127222.2	ENSP00000353362		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19175

AN:

151986

Hom.:

1535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.0528

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.187

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0722

Gnomad OTH

AF:

0.101

GnomAD4 exome

AF:

0.0967

AC:

73233

AN:

757352

Hom.:

4699

AF XY:

0.0985

AC XY:

38456

AN XY:

390552

show subpopulations

Gnomad4 AFR exome

AF:

0.208

Gnomad4 AMR exome

AF:

0.124

Gnomad4 ASJ exome

AF:

0.0581

Gnomad4 EAS exome

AF:

0.251

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.107

Gnomad4 NFE exome

AF:

0.0719

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.126

AC:

19205

AN:

152104

Hom.:

1539

Cov.:

AF XY:

0.130

AC XY:

9670

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.207

Gnomad4 AMR

AF:

0.118

Gnomad4 ASJ

AF:

0.0528

Gnomad4 EAS

AF:

0.261

Gnomad4 SAS

AF:

0.186

Gnomad4 FIN

AF:

0.117

Gnomad4 NFE

AF:

0.0722

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.0806

Hom.:

1266

Bravo

AF:

0.127

Asia WGS

AF:

0.211

AC:

732

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.8

DANN

Benign

0.77

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