rs1054400971
Variant names:
Variant summary
Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_021098.3(CACNA1H):c.4929+5G>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 0.00000684 in 1,608,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
CACNA1H
NM_021098.3 splice_region, intron
NM_021098.3 splice_region, intron
Scores
2
Splicing: ADA: 0.9985
1
1
Clinical Significance
Conservation
PhyloP100: 2.15
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: Benign. The variant received -8 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BS2
High AC in GnomAdExome4 at 9 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1H | NM_021098.3 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | ENST00000348261.11 | NP_066921.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1H | ENST00000348261.11 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | 1 | NM_021098.3 | ENSP00000334198.7 | |||
| CACNA1H | ENST00000569107.6 | c.4944+5G>A | splice_region_variant, intron_variant | Intron 26 of 33 | 1 | ENSP00000454990.2 | ||||
| CACNA1H | ENST00000711493.1 | c.4947+5G>A | splice_region_variant, intron_variant | Intron 26 of 33 | ENSP00000518778.1 | |||||
| CACNA1H | ENST00000565831.7 | c.4911+5G>A | splice_region_variant, intron_variant | Intron 26 of 33 | 1 | ENSP00000455840.1 | ||||
| CACNA1H | ENST00000711450.1 | c.4944+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | ENSP00000518762.1 | |||||
| CACNA1H | ENST00000564231.6 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | 1 | ENSP00000457555.2 | ||||
| CACNA1H | ENST00000638323.1 | c.4890+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | 5 | ENSP00000492267.1 | ||||
| CACNA1H | ENST00000562079.6 | c.4911+5G>A | splice_region_variant, intron_variant | Intron 26 of 33 | 1 | ENSP00000454581.2 | ||||
| CACNA1H | ENST00000711438.1 | c.4872+5G>A | splice_region_variant, intron_variant | Intron 26 of 33 | ENSP00000518754.1 | |||||
| CACNA1H | ENST00000711482.1 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 35 | ENSP00000518771.1 | |||||
| CACNA1H | ENST00000711485.1 | c.4911+5G>A | splice_region_variant, intron_variant | Intron 26 of 34 | ENSP00000518774.1 | |||||
| CACNA1H | ENST00000711455.1 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 35 | ENSP00000518768.1 | |||||
| CACNA1H | ENST00000711483.1 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | ENSP00000518772.1 | |||||
| CACNA1H | ENST00000711456.1 | c.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 33 | ENSP00000518769.1 | |||||
| CACNA1H | ENST00000621827.2 | n.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 36 | 6 | ENSP00000518766.1 | ||||
| CACNA1H | ENST00000637236.3 | n.*881+5G>A | splice_region_variant, intron_variant | Intron 26 of 33 | 5 | ENSP00000492650.2 | ||||
| CACNA1H | ENST00000639478.1 | n.*10+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | 5 | ENSP00000491945.1 | ||||
| CACNA1H | ENST00000640028.1 | n.*2780+5G>A | splice_region_variant, intron_variant | Intron 27 of 34 | 5 | ENSP00000491488.1 | ||||
| CACNA1H | ENST00000711442.1 | n.*4373+5G>A | splice_region_variant, intron_variant | Intron 25 of 33 | ENSP00000518758.1 | |||||
| CACNA1H | ENST00000711448.1 | n.4911+5G>A | splice_region_variant, intron_variant | Intron 26 of 35 | ENSP00000518760.1 | |||||
| CACNA1H | ENST00000711449.1 | n.4911+5G>A | splice_region_variant, intron_variant | Intron 26 of 34 | ENSP00000518761.1 | |||||
| CACNA1H | ENST00000711451.1 | n.5006+5G>A | splice_region_variant, intron_variant | Intron 27 of 35 | ENSP00000518763.1 | |||||
| CACNA1H | ENST00000711452.1 | n.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 35 | ENSP00000518764.1 | |||||
| CACNA1H | ENST00000711453.1 | n.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 35 | ENSP00000518765.1 | |||||
| CACNA1H | ENST00000711484.1 | n.4911+5G>A | splice_region_variant, intron_variant | Intron 26 of 34 | ENSP00000518773.1 | |||||
| CACNA1H | ENST00000711486.1 | n.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 36 | ENSP00000518775.1 | |||||
| CACNA1H | ENST00000711487.1 | n.4929+5G>A | splice_region_variant, intron_variant | Intron 27 of 35 | ENSP00000518776.1 | |||||
| CACNA1H | ENST00000711488.1 | n.4988+5G>A | splice_region_variant, intron_variant | Intron 26 of 34 | ENSP00000518777.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152222
Hom.:
Cov.:
33
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:
GnomAD2 exomes AF: 0.00000420 AC: 1AN: 238230 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
238230
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: 0.00000618 AC: 9AN: 1456340Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 723984 show subpopulations
GnomAD4 exome
AF:
AC:
9
AN:
1456340
Hom.:
Cov.:
31
AF XY:
AC XY:
3
AN XY:
723984
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33416
American (AMR)
AF:
AC:
1
AN:
44234
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26004
East Asian (EAS)
AF:
AC:
0
AN:
39550
South Asian (SAS)
AF:
AC:
0
AN:
85222
European-Finnish (FIN)
AF:
AC:
0
AN:
51708
Middle Eastern (MID)
AF:
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
AC:
8
AN:
1110282
Other (OTH)
AF:
AC:
0
AN:
60168
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.464
Heterozygous variant carriers
0
1
2
3
4
5
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 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74362 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
152222
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74362
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41462
American (AMR)
AF:
AC:
1
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5176
South Asian (SAS)
AF:
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68044
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:not provided
- -
Sep 24, 2020
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016) -
Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Apr 01, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Jan 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change falls in intron 27 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 (no rsID available, gnomAD 0.003%). 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: 460133). 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
Pathogenic
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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