rs1064794262

Positions:

chr19-13303830-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001127222.2(CACNA1A):c.2039_2040del(p.Gln680ArgfsTer100) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.91

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-13303830-CCT-C is Pathogenic according to our data. Variant chr19-13303830-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.2039_2040del	p.Gln680ArgfsTer100	frameshift_variant	16/47	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.2039_2040del	p.Gln680ArgfsTer100	frameshift_variant	16/47	1	NM_001127222.2	ENSP00000353362		O00555-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249250

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135210

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461638

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2023	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with episodic ataxia in multiple families and has been confirmed to occur de novo in one individual. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27479843, 20396531, 27667184, 20129625, 28566750, 11960817, 32581362, 10371528, 12420090) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

Developmental and epileptic encephalopathy, 42

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 10, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 30, 2022	_x000D_ Criteria applied: PVS1, PS4_MOD, PS2_SUP -

Episodic ataxia type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Oct 25, 2022

PVS1, PS4_Moderate, PM2 -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 420056). This variant is also known as "deletion AG 2259-60" and c.2145_2148delAG. This premature translational stop signal has been observed in individual(s) with episodic ataxia type 2 (PMID: 10371528, 12420090, 20129625, 20396531, 28566750). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln681Argfs*100) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). -

Epileptic encephalopathy;C3806482:Recurrent respiratory infections;C4082299:Bulbar palsy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.2042_2043delAG (p.Q681Rfs*100) alteration, located in exon 16 (coding exon 16) of the CACNA1A gene, consists of a deletion of 2 nucleotides from position 2042 to 2043, causing a translational frameshift with a predicted alternate stop codon after 100 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ for episodic ataxia, type 2; however, its clinical significance for CACNA1A-related neurologic disorder is uncertain, and it is unlikely to be causative of CACNA1A-related spinocerebellar ataxia. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/249250) total alleles studied. The highest observed frequency was 0.001% (1/113012) of European (non-Finnish) alleles. This variant was reported in multiple individuals with recurrent episodes of ataxia and has been shown to segregate with disease in one family with varying severities of episodic ataxia type 2 (Denier, 1999; Kim, 2006; Mantuano, 2010; Sintas, 2017). Additionally, this variant has been determined to be the result of a de novo mutation in two individuals with episodic ataxia and nystagmus (van den Maagdenberg, 2002; Zhang, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

CACNA1A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2023

The CACNA1A c.2039_2040delAG variant is predicted to result in a frameshift and premature protein termination (p.Gln680Argfs*100). This variant is alternatively referred to as c.2042_2043delAG (p.Gln681Argfs*100). This variant has been reported de novo in an individual from an intellectual disability cohort (Table S2, Lelieveld et al. 2016. PubMed ID: 27479843). It has also been reported in three individuals with episodic ataxia; in one of these individuals the variant was confirmed to have arisen de novo (referred to as c.2137_2318delAG, Family 2, Figure 1, van den Maagdenberg et al. 2002. PubMed ID: 12420090; Table 1, Sintas et al. 2017. PubMed ID: 28566750; Table 1, Zhang et al. 2020. PubMed ID: 33425808). One individual with episodic ataxia that harbored this variant also exhibited nystagmus, and language developmental delay, but was not reported to have seizures (Table 1, Zhang et al. 2020. PubMed ID: 33425808). It has also been reported in an individual undergoing exome sequencing (Table S2, Turro et al. 2020. PubMed ID: 32581362). This variant is reported in 1 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/19-13414644-CCT-C). Frameshift variants in CACNA1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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