rs371972266
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_001127222.2(CACNA1A):c.5868C>T(p.Tyr1956Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,706 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 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
CACNA1A
NM_001127222.2 synonymous
NM_001127222.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.821
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 -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 19-13214305-G-A is Benign according to our data. Variant chr19-13214305-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 515383.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
BP7
Synonymous conserved (PhyloP=-0.821 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000919 (14/152324) while in subpopulation EAS AF= 0.00232 (12/5180). AF 95% confidence interval is 0.00134. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1A | ENST00000360228.11 | c.5868C>T | p.Tyr1956Tyr | synonymous_variant | 40/47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
| CACNA1A | ENST00000638029.1 | c.5886C>T | p.Tyr1962Tyr | synonymous_variant | 41/48 | 5 | ENSP00000489829.1 | |||
| CACNA1A | ENST00000573710.7 | c.5874C>T | p.Tyr1958Tyr | synonymous_variant | 40/47 | 5 | ENSP00000460092.3 | |||
| CACNA1A | ENST00000635727.1 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/47 | 5 | ENSP00000490001.1 | |||
| CACNA1A | ENST00000637769.1 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/47 | 1 | ENSP00000489778.1 | |||
| CACNA1A | ENST00000636012.1 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/46 | 5 | ENSP00000490223.1 | |||
| CACNA1A | ENST00000637736.1 | c.5730C>T | p.Tyr1910Tyr | synonymous_variant | 39/46 | 5 | ENSP00000489861.1 | |||
| CACNA1A | ENST00000636389.1 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/47 | 5 | ENSP00000489992.1 | |||
| CACNA1A | ENST00000637432.1 | c.5886C>T | p.Tyr1962Tyr | synonymous_variant | 41/48 | 5 | ENSP00000490617.1 | |||
| CACNA1A | ENST00000636549.1 | c.5877C>T | p.Tyr1959Tyr | synonymous_variant | 41/48 | 5 | ENSP00000490578.1 | |||
| CACNA1A | ENST00000637927.1 | c.5874C>T | p.Tyr1958Tyr | synonymous_variant | 40/47 | 5 | ENSP00000489715.1 | |||
| CACNA1A | ENST00000635895.1 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/47 | 5 | ENSP00000490323.1 | |||
| CACNA1A | ENST00000638009.2 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/47 | 1 | ENSP00000489913.1 | |||
| CACNA1A | ENST00000637276.1 | c.5871C>T | p.Tyr1957Tyr | synonymous_variant | 40/46 | 5 | ENSP00000489777.1 | |||
| CACNA1A | ENST00000636768.1 | n.*170C>T | non_coding_transcript_exon_variant | 5/10 | 5 | ENSP00000490190.2 | ||||
| CACNA1A | ENST00000636768.1 | n.*170C>T | 3_prime_UTR_variant | 5/10 | 5 | ENSP00000490190.2 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000121 AC: 30AN: 248046Hom.: 0 AF XY: 0.0000965 AC XY: 13AN XY: 134734
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1460382Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 726544
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GnomAD4 genome 0.0000919 AC: 14AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 14, 2017 | - - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2023 | - - |
Inborn genetic diseases Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2017 | This alteration is classified as likely 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. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at