rs773966897
Variant names:
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_021098.3(CACNA1H):c.2603+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CACNA1H
NM_021098.3 splice_region, intron
NM_021098.3 splice_region, intron
Scores
2
Splicing: ADA: 0.00006001
2
Clinical Significance
Conservation
PhyloP100: 0.570
Publications
0 publications found
Genes affected
CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]
CACNA1H Gene-Disease associations (from GenCC):
- hyperaldosteronism, familial, type IVInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- childhood absence epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- epilepsy, childhood absence, susceptibility to, 6Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1H | NM_021098.3 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENST00000348261.11 | NP_066921.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1H | ENST00000348261.11 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | 1 | NM_021098.3 | ENSP00000334198.7 | |||
| CACNA1H | ENST00000569107.6 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | 1 | ENSP00000454990.2 | ||||
| CACNA1H | ENST00000711493.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | ENSP00000518778.1 | |||||
| CACNA1H | ENST00000565831.7 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | 1 | ENSP00000455840.1 | ||||
| CACNA1H | ENST00000711450.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENSP00000518762.1 | |||||
| CACNA1H | ENST00000564231.6 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | 1 | ENSP00000457555.2 | ||||
| CACNA1H | ENST00000638323.1 | c.2564+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | 5 | ENSP00000492267.1 | ||||
| CACNA1H | ENST00000562079.6 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | 1 | ENSP00000454581.2 | ||||
| CACNA1H | ENST00000711438.1 | c.2564+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | ENSP00000518754.1 | |||||
| CACNA1H | ENST00000711482.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518771.1 | |||||
| CACNA1H | ENST00000711485.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENSP00000518774.1 | |||||
| CACNA1H | ENST00000711455.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518768.1 | |||||
| CACNA1H | ENST00000711483.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENSP00000518772.1 | |||||
| CACNA1H | ENST00000711456.1 | c.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | ENSP00000518769.1 | |||||
| CACNA1H | ENST00000621827.2 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 36 | 6 | ENSP00000518766.1 | ||||
| CACNA1H | ENST00000637236.3 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 33 | 5 | ENSP00000492650.2 | ||||
| CACNA1H | ENST00000639478.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | 5 | ENSP00000491945.1 | ||||
| CACNA1H | ENST00000640028.1 | n.*516+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | 5 | ENSP00000491488.1 | ||||
| CACNA1H | ENST00000711442.1 | n.*2050+3G>A | splice_region_variant, intron_variant | Intron 10 of 33 | ENSP00000518758.1 | |||||
| CACNA1H | ENST00000711448.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518760.1 | |||||
| CACNA1H | ENST00000711449.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENSP00000518761.1 | |||||
| CACNA1H | ENST00000711451.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518763.1 | |||||
| CACNA1H | ENST00000711452.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518764.1 | |||||
| CACNA1H | ENST00000711453.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518765.1 | |||||
| CACNA1H | ENST00000711484.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENSP00000518773.1 | |||||
| CACNA1H | ENST00000711486.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 36 | ENSP00000518775.1 | |||||
| CACNA1H | ENST00000711487.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 35 | ENSP00000518776.1 | |||||
| CACNA1H | ENST00000711488.1 | n.2603+3G>A | splice_region_variant, intron_variant | Intron 11 of 34 | ENSP00000518777.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.00000815 AC: 2AN: 245410 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
245410
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1449802Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 719060 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1449802
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
719060
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33312
American (AMR)
AF:
AC:
2
AN:
44440
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25856
East Asian (EAS)
AF:
AC:
0
AN:
39376
South Asian (SAS)
AF:
AC:
0
AN:
85738
European-Finnish (FIN)
AF:
AC:
0
AN:
52134
Middle Eastern (MID)
AF:
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1103358
Other (OTH)
AF:
AC:
0
AN:
59848
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Jan 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change falls in intron 11 of the CACNA1H gene. It does not directly change the encoded amino acid sequence of the CACNA1H protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs773966897, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 566036). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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