rs1064794262

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001127222.2(CACNA1A):c.2039_2040delAG(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:12

Conservation

PhyloP100: 4.91

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

episodic ataxia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
benign paroxysmal torticollis of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial or sporadic hemiplegic migraine
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 420056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2039_2040delAG	p.Gln680ArgfsTer100	frameshift_variant	Exon 16 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.2039_2040delAG	p.Gln680ArgfsTer100	frameshift_variant	Exon 16 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.2042_2043delAG	p.Gln681ArgfsTer103	frameshift_variant	Exon 16 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.2045_2046delAG	p.Gln682ArgfsTer100	frameshift_variant	Exon 16 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.1901_1902delAG	p.Gln634ArgfsTer100	frameshift_variant	Exon 15 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.2042_2043delAG	p.Gln681ArgfsTer103	frameshift_variant	Exon 16 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.2045_2046delAG	p.Gln682ArgfsTer100	frameshift_variant	Exon 16 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.2042_2043delAG	p.Gln681ArgfsTer100	frameshift_variant	Exon 16 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.2042_2043delAG		non_coding_transcript_exon_variant	Exon 16 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.2039_2040delAG		non_coding_transcript_exon_variant	Exon 16 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249250

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111814

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jun 23, 2023

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 09, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 42

Pathogenic:3

Feb 10, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PVS1, PS4_MOD, PS2_SUP -

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic ataxia type 2

Pathogenic:1

Oct 25, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4_Moderate, PM2 -

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

Pathogenic:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Pathogenic:1

Feb 13, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

4.9

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over