rs759576380
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001127222.2(CACNA1A):c.6715C>T(p.Arg2239Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,544,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
CACNA1A
NM_001127222.2 missense
NM_001127222.2 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 0.300
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 Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.6715C>T | p.Arg2239Trp | missense_variant | 46/47 | ENST00000360228.11 | NP_001120694.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.6715C>T | p.Arg2239Trp | missense_variant | 46/47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.6733C>T | p.Arg2245Trp | missense_variant | 47/48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.6721C>T | p.Arg2241Trp | missense_variant | 46/47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.6718C>T | p.Arg2240Trp | missense_variant | 46/47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.6718C>T | p.Arg2240Trp | missense_variant | 46/47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.6682C>T | p.Arg2228Trp | missense_variant | 45/46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.6577C>T | p.Arg2193Trp | missense_variant | 45/46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.6718C>T | p.Arg2240Trp | missense_variant | 46/47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.6733C>T | p.Arg2245Trp | missense_variant | 47/48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.6724C>T | p.Arg2242Trp | missense_variant | 47/48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.6721C>T | p.Arg2241Trp | missense_variant | 46/47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.6718C>T | p.Arg2240Trp | missense_variant | 46/47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.6718C>T | p.Arg2240Trp | missense_variant | 46/47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.6682C>T | p.Arg2228Trp | missense_variant | 45/46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151912Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
5
AN:
151912
Hom.:
Cov.:
31
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: 0.0000542 AC: 8AN: 147666Hom.: 0 AF XY: 0.0000492 AC XY: 4AN XY: 81340
GnomAD3 exomes
AF:
AC:
8
AN:
147666
Hom.:
AF XY:
AC XY:
4
AN XY:
81340
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: 0.000130 AC: 181AN: 1392190Hom.: 0 Cov.: 36 AF XY: 0.000134 AC XY: 92AN XY: 688096
GnomAD4 exome
AF:
AC:
181
AN:
1392190
Hom.:
Cov.:
36
AF XY:
AC XY:
92
AN XY:
688096
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 AF: 0.0000329 AC: 5AN: 151912Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2AN XY: 74178
GnomAD4 genome
AF:
AC:
5
AN:
151912
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
74178
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:
ExAC
AF:
AC:
8
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 04, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31719132, 28492532) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2019 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2019 | The p.R2240W variant (also known as c.6718C>T), located in coding exon 46 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6718. The arginine at codon 2240 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 | May 08, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
0.37
.;.;Loss of methylation at R2240 (P = 0.0068);Loss of methylation at R2240 (P = 0.0068);Loss of methylation at R2240 (P = 0.0068);.;.;Loss of methylation at R2240 (P = 0.0068);.;.;.;.;Loss of methylation at R2240 (P = 0.0068);.;.;.;.;.;
MVP
MPC
0.83
ClinPred
D
GERP RS
Varity_R
gMVP
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