19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTG
Variant summary
Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2
The NM_001127222.2(CACNA1A):c.6955_6975delCAGCAGCAGCAGCAGCAGCAG(p.Gln2319_Gln2325del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,430,526 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 0)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
CACNA1A
NM_001127222.2 conservative_inframe_deletion
NM_001127222.2 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.785
Publications
10 publications found
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]
CACNA1A Gene-Disease associations (from GenCC):
- episodic ataxia type 2Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- undetermined early-onset epileptic encephalopathyInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
- developmental and epileptic encephalopathy, 42Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- migraine, familial hemiplegic, 1Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- spinocerebellar ataxia type 6Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- benign paroxysmal torticollis of infancyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial or sporadic hemiplegic migraineInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Lennox-Gastaut syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -8 ACMG points.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000345 (51/147904) while in subpopulation AFR AF = 0.000871 (35/40206). AF 95% confidence interval is 0.000643. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
BS2
High AC in GnomAd4 at 51 AD gene.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1A | ENST00000360228.11 | c.6955_6975delCAGCAGCAGCAGCAGCAGCAG | p.Gln2319_Gln2325del | conservative_inframe_deletion | Exon 47 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
| CACNA1A | ENST00000638029.1 | c.6973_6993delCAGCAGCAGCAGCAGCAGCAG | p.Gln2325_Gln2331del | conservative_inframe_deletion | Exon 48 of 48 | 5 | ENSP00000489829.1 | |||
| CACNA1A | ENST00000573710.7 | c.6961_6981delCAGCAGCAGCAGCAGCAGCAG | p.Gln2321_Gln2327del | conservative_inframe_deletion | Exon 47 of 47 | 5 | ENSP00000460092.3 | |||
| CACNA1A | ENST00000635727.1 | c.6958_6978delCAGCAGCAGCAGCAGCAGCAG | p.Gln2320_Gln2326del | conservative_inframe_deletion | Exon 47 of 47 | 5 | ENSP00000490001.1 | |||
| CACNA1A | ENST00000637769.1 | c.6958_6978delCAGCAGCAGCAGCAGCAGCAG | p.Gln2320_Gln2326del | conservative_inframe_deletion | Exon 47 of 47 | 1 | ENSP00000489778.1 | |||
| CACNA1A | ENST00000636012.1 | c.6922_6942delCAGCAGCAGCAGCAGCAGCAG | p.Gln2308_Gln2314del | conservative_inframe_deletion | Exon 46 of 46 | 5 | ENSP00000490223.1 | |||
| CACNA1A | ENST00000637736.1 | c.6817_6837delCAGCAGCAGCAGCAGCAGCAG | p.Gln2273_Gln2279del | conservative_inframe_deletion | Exon 46 of 46 | 5 | ENSP00000489861.1 | |||
| CACNA1A | ENST00000636768.2 | n.*1216_*1236delCAGCAGCAGCAGCAGCAGCAG | non_coding_transcript_exon_variant | Exon 45 of 45 | 5 | ENSP00000490190.2 | ||||
| CACNA1A | ENST00000713789.1 | n.*2134_*2154delCAGCAGCAGCAGCAGCAGCAG | non_coding_transcript_exon_variant | Exon 47 of 47 | ENSP00000519091.1 | |||||
| CACNA1A | ENST00000636389.1 | c.*41_*61delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 47 of 47 | 5 | ENSP00000489992.1 | ||||
| CACNA1A | ENST00000637432.1 | c.*167_*187delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 48 of 48 | 5 | ENSP00000490617.1 | ||||
| CACNA1A | ENST00000635895.1 | c.*167_*187delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 47 of 47 | 5 | ENSP00000490323.1 | ||||
| CACNA1A | ENST00000638009.2 | c.*167_*187delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 47 of 47 | 1 | ENSP00000489913.1 | ||||
| CACNA1A | ENST00000637276.1 | c.*167_*187delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 46 of 46 | 5 | ENSP00000489777.1 | ||||
| CACNA1A | ENST00000636768.2 | n.*1216_*1236delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 45 of 45 | 5 | ENSP00000490190.2 | ||||
| CACNA1A | ENST00000713789.1 | n.*2134_*2154delCAGCAGCAGCAGCAGCAGCAG | 3_prime_UTR_variant | Exon 47 of 47 | ENSP00000519091.1 | |||||
| CACNA1A | ENST00000636549.1 | c.*167_*187delCAGCAGCAGCAGCAGCAGCAG | downstream_gene_variant | 5 | ENSP00000490578.1 | |||||
| CACNA1A | ENST00000637927.1 | c.*167_*187delCAGCAGCAGCAGCAGCAGCAG | downstream_gene_variant | 5 | ENSP00000489715.1 |
Frequencies
GnomAD3 genomes 0.000352 AC: 52AN: 147802Hom.: 0 Cov.: 0 show subpopulations
GnomAD3 genomes
AF:
AC:
52
AN:
147802
Hom.:
Cov.:
0
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:
GnomAD4 exome AF: 0.000156 AC: 200AN: 1282622Hom.: 0 AF XY: 0.000184 AC XY: 116AN XY: 631208 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
200
AN:
1282622
Hom.:
AF XY:
AC XY:
116
AN XY:
631208
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
13
AN:
24918
American (AMR)
AF:
AC:
4
AN:
24092
Ashkenazi Jewish (ASJ)
AF:
AC:
2
AN:
21710
East Asian (EAS)
AF:
AC:
12
AN:
29580
South Asian (SAS)
AF:
AC:
36
AN:
65408
European-Finnish (FIN)
AF:
AC:
19
AN:
33312
Middle Eastern (MID)
AF:
AC:
1
AN:
3750
European-Non Finnish (NFE)
AF:
AC:
101
AN:
1026754
Other (OTH)
AF:
AC:
12
AN:
53098
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.383
Heterozygous variant carriers
0
10
19
29
38
48
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.000345 AC: 51AN: 147904Hom.: 0 Cov.: 0 AF XY: 0.000361 AC XY: 26AN XY: 72002 show subpopulations
GnomAD4 genome
AF:
AC:
51
AN:
147904
Hom.:
Cov.:
0
AF XY:
AC XY:
26
AN XY:
72002
show subpopulations
African (AFR)
AF:
AC:
35
AN:
40206
American (AMR)
AF:
AC:
4
AN:
14968
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3436
East Asian (EAS)
AF:
AC:
0
AN:
4816
South Asian (SAS)
AF:
AC:
0
AN:
4704
European-Finnish (FIN)
AF:
AC:
4
AN:
9952
Middle Eastern (MID)
AF:
AC:
0
AN:
276
European-Non Finnish (NFE)
AF:
AC:
8
AN:
66606
Other (OTH)
AF:
AC:
0
AN:
2044
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.531
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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