rs371757002
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_001127222.2(CACNA1A):c.2754C>T(p.Gly918=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,592,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000058 ( 0 hom. )
Consequence
CACNA1A
NM_001127222.2 synonymous
NM_001127222.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.794
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 -10 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 19-13298879-G-A is Benign according to our data. Variant chr19-13298879-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387665.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=-0.794 with no splicing effect.
BS2
High AC in GnomAdExome4 at 84 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.2754C>T | p.Gly918= | synonymous_variant | 19/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.2754C>T | p.Gly918= | synonymous_variant | 19/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000739 AC: 16AN: 216464Hom.: 0 AF XY: 0.0000497 AC XY: 6AN XY: 120756
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GnomAD4 exome AF: 0.0000583 AC: 84AN: 1440822Hom.: 0 Cov.: 32 AF XY: 0.0000516 AC XY: 37AN XY: 716986
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74320
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2016 | A variant of uncertain significance has been identified in the CACNA1A gene. The c.2757 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.2757 C>T variant was not observed with any significant frequency in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is not conserved. Several in-silico splice prediction models predict that c.2757 C>T creates a cryptic donor site which may supplant the natural donor site in exon 19 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
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DANN
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at