NM_001127222.2:c.2039_2040delAG

Variant names:

• chr19-13303830-CCT-C
• rs1064794262
• NM_001127222.2:c.2039_2040delAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.91

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2039_2040delAG	p.Gln680ArgfsTer100	frameshift_variant	Exon 16 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249250 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135210

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: 2 AN: 1461638 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727118

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.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

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. -

Oct 31, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Developmental and epileptic encephalopathy, 42 Pathogenic:2

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 -

Feb 10, 2022

MGZ Medical Genetics Center

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

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

Other links and lift over

dbSNP: rs1064794262; hg19: chr19-13414644;