16-1204361-A-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_021098.3(CACNA1H):c.2354A>T(p.Lys785Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,576,242 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0029 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0039 ( 21 hom. )
Consequence
CACNA1H
NM_021098.3 missense
NM_021098.3 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 1.97
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.03796467).
BP6
Variant 16-1204361-A-T is Benign according to our data. Variant chr16-1204361-A-T is described in ClinVar as [Benign]. Clinvar id is 460063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1204361-A-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00295 (449/152370) while in subpopulation AMR AF= 0.0049 (75/15312). AF 95% confidence interval is 0.00401. There are 2 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 449 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1H | NM_021098.3 | c.2354A>T | p.Lys785Met | missense_variant | 10/35 | ENST00000348261.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.2354A>T | p.Lys785Met | missense_variant | 10/35 | 1 | NM_021098.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00295 AC: 449AN: 152252Hom.: 2 Cov.: 33
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GnomAD3 exomes AF: 0.00357 AC: 774AN: 216636Hom.: 3 AF XY: 0.00362 AC XY: 424AN XY: 117272
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GnomAD4 exome AF: 0.00389 AC: 5537AN: 1423872Hom.: 21 Cov.: 32 AF XY: 0.00397 AC XY: 2794AN XY: 704212
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GnomAD4 genome AF: 0.00295 AC: 449AN: 152370Hom.: 2 Cov.: 33 AF XY: 0.00283 AC XY: 211AN XY: 74520
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 20, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | CACNA1H: BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;.
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;M;M
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D
Sift4G
Uncertain
D;.;D;D
Polyphen
D;.;D;D
Vest4
MVP
ClinPred
T
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