rs527246699
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2
The NM_001127222.2(CACNA1A):c.1038C>T(p.Ile346Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,012 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
CACNA1A
NM_001127222.2 synonymous
NM_001127222.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0340
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP7
Synonymous conserved (PhyloP=-0.034 with no splicing effect.
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1A | NM_001127222.2 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | ENST00000360228.11 | NP_001120694.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1A | ENST00000360228.11 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
| CACNA1A | ENST00000638029.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/48 | 5 | ENSP00000489829.1 | |||
| CACNA1A | ENST00000573710.7 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 5 | ENSP00000460092.3 | |||
| CACNA1A | ENST00000635727.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 5 | ENSP00000490001.1 | |||
| CACNA1A | ENST00000637769.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 1 | ENSP00000489778.1 | |||
| CACNA1A | ENST00000636012.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/46 | 5 | ENSP00000490223.1 | |||
| CACNA1A | ENST00000637736.1 | c.897C>T | p.Ile299Ile | synonymous_variant | 6/46 | 5 | ENSP00000489861.1 | |||
| CACNA1A | ENST00000636389.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 5 | ENSP00000489992.1 | |||
| CACNA1A | ENST00000637432.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/48 | 5 | ENSP00000490617.1 | |||
| CACNA1A | ENST00000636549.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/48 | 5 | ENSP00000490578.1 | |||
| CACNA1A | ENST00000637927.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 5 | ENSP00000489715.1 | |||
| CACNA1A | ENST00000635895.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 5 | ENSP00000490323.1 | |||
| CACNA1A | ENST00000638009.2 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/47 | 1 | ENSP00000489913.1 | |||
| CACNA1A | ENST00000637276.1 | c.1038C>T | p.Ile346Ile | synonymous_variant | 7/46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
6
AN:
152186
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000205 AC: 5AN: 243708Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132094
GnomAD3 exomes
AF:
AC:
5
AN:
243708
Hom.:
AF XY:
AC XY:
3
AN XY:
132094
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000247 AC: 36AN: 1458708Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24AN XY: 725330
GnomAD4 exome
AF:
AC:
36
AN:
1458708
Hom.:
Cov.:
30
AF XY:
AC XY:
24
AN XY:
725330
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000394 AC: 6AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74472
GnomAD4 genome
AF:
AC:
6
AN:
152304
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74472
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 06, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at