16-1217937-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_021098.3(CACNA1H):āc.5342C>Gā(p.Pro1781Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000854 in 1,604,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 34)
Exomes š: 0.000090 ( 0 hom. )
Consequence
CACNA1H
NM_021098.3 missense
NM_021098.3 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 4.83
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1H | NM_021098.3 | c.5342C>G | p.Pro1781Arg | missense_variant | 32/35 | ENST00000348261.11 | NP_066921.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.5342C>G | p.Pro1781Arg | missense_variant | 32/35 | 1 | NM_021098.3 | ENSP00000334198 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152254Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000515 AC: 12AN: 233014Hom.: 0 AF XY: 0.0000629 AC XY: 8AN XY: 127220
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GnomAD4 exome AF: 0.0000902 AC: 131AN: 1452666Hom.: 0 Cov.: 31 AF XY: 0.0000873 AC XY: 63AN XY: 721914
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152254Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74382
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2023 | The c.5342C>G (p.P1781R) alteration is located in exon 32 (coding exon 31) of the CACNA1H gene. This alteration results from a C to G substitution at nucleotide position 5342, causing the proline (P) at amino acid position 1781 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 07, 2022 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1781 of the CACNA1H protein (p.Pro1781Arg). This variant is present in population databases (rs372601783, gnomAD 0.01%). 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: 567636). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D
Sift4G
Pathogenic
D;.;D;D
Polyphen
D;.;D;D
Vest4
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at