rs61732194
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_021098.3(CACNA1H):āc.5494C>Gā(p.Leu1832Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,398,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L1832L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Exomes š: 0.000041 ( 0 hom. )
Consequence
CACNA1H
NM_021098.3 missense
NM_021098.3 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 4.70
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAdExome4 at 58 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1H | NM_021098.3 | c.5494C>G | p.Leu1832Val | missense_variant | 33/35 | ENST00000348261.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.5494C>G | p.Leu1832Val | missense_variant | 33/35 | 1 | NM_021098.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD3 exomes AF: 0.0000191 AC: 3AN: 157360Hom.: 0 AF XY: 0.0000120 AC XY: 1AN XY: 83298
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GnomAD4 exome AF: 0.0000415 AC: 58AN: 1398714Hom.: 0 Cov.: 32 AF XY: 0.0000377 AC XY: 26AN XY: 689960
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
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Cov.:
34
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | The c.5494C>G (p.L1832V) alteration is located in exon 33 (coding exon 32) of the CACNA1H gene. This alteration results from a C to G substitution at nucleotide position 5494, causing the leucine (L) at amino acid position 1832 to be replaced by a valine (V). 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 | Invitae | Oct 08, 2021 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 1832 of the CACNA1H protein (p.Leu1832Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N
REVEL
Pathogenic
Sift
Benign
T;.;T;T
Sift4G
Benign
T;.;T;T
Polyphen
D;.;D;D
Vest4
MutPred
Loss of helix (P = 0.028);.;.;.;
MVP
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