rs749638821
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2
The NM_001127222.2(CACNA1A):c.6656_6658del(p.His2219del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00156 in 1,373,696 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H2219HH) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00063 ( 1 hom., cov: 27)
Exomes 𝑓: 0.0017 ( 1 hom. )
Consequence
CACNA1A
NM_001127222.2 inframe_deletion
NM_001127222.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.98
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_001127222.2. Strenght limited to Supporting due to length of the change: 1aa.
BP6
?
Variant 19-13208877-GGAT-G is Benign according to our data. Variant chr19-13208877-GGAT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377042.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}. Variant chr19-13208877-GGAT-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000631 (95/150506) while in subpopulation AMR AF= 0.000858 (13/15154). AF 95% confidence interval is 0.000507. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 95 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.6656_6658del | p.His2219del | inframe_deletion | 46/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.6656_6658del | p.His2219del | inframe_deletion | 46/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000618 AC: 93AN: 150402Hom.: 1 Cov.: 27
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GnomAD3 exomes AF: 0.00226 AC: 265AN: 117448Hom.: 0 AF XY: 0.00219 AC XY: 140AN XY: 63980
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GnomAD4 exome AF: 0.00167 AC: 2044AN: 1223190Hom.: 1 AF XY: 0.00169 AC XY: 1023AN XY: 604492
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 30, 2016 | - - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 377042). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.6659_6661del, results in the deletion of 1 amino acid(s) of the CACNA1A protein (p.His2220del), but otherwise preserves the integrity of the reading frame. - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
CACNA1A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 18, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at